INTRODUCTION: A GRANDMOTHER’S PRAYER
1. In a wide-ranging interview to promote his memoirs, Lanzmann said of his masterpiece film about the Holocaust, “I wanted to get as close as possible to death. No personal accounts are told in Shoah, no anecdotes. It’s only about death. The film is not about the survivors.” “ ‘Shoah’ Director Claude Lanzmann: ‘Death Has Always Been a Scandal,’ ” Spiegel, September 10, 2010, http://www.spiegel.de/international/zeitgeist/shoah-director-claude-lanzmann-death-has-always-been-a-scandal-a-716722.html.
2. The study looked at three concepts about death that children come to understand before they are seven years old: irreversibility, nonfunctionality, and universality. M. W. Speece and S. B. Brent, “Children’s Understanding of Death: A Review of Three Components of a Death Concept,” Child Development 55, no. 5 (October 1984): 1671–86, https://www.ncbi.nlm.nih.gov/pubmed/6510050.
3. The author attended the birth of her daughter’s first child along with her son-in-law. R. M. Henig, “The Ecstasy and the Agony of Being a Grandmother,” New York Times, December 27, 2018, https://www.nytimes.com/2018/12/27/style/self-care/becoming-a-grandmother.html.
4. The film’s exhortations to make the most of every day took on a darker hue after the suicide of its star, Robin Williams. P. Weir, director, Dead Poets Society, United States: Touchstone Pictures, 1999.
5. The author argues that rather than focusing on cancer and cardiovascular issues, medical research should be focusing on “reducing ageing and age-related morbidity, thereby increasing both our health and our wealth.” G. C. Brown, “Living Too Long,” EMBO Reports 16, no. 2 (February 2015): 137–41, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4328740/.
6. In a survey coconducted by the Economist, the majority of respondents from four countries expressed the wish to die at home, although only a small number thought that they would do so. With the exception of Brazilians, most felt that dying without pain was more important than extending life. “A Better Way to Care for the Dying,” Economist, April 29, 2017, https://www.economist.com/international/2017/04/29/a-better-way-to-care-for-the-dying.
7. See my conflict disclosures at the end of this book and at https://genetics.med.harvard.edu/sinclair-test/people/sinclair-other.php.
8. My editor made me write self-centered things about myself to give me credibility. I hope she doesn’t see this endnote and make me delete it.
9. In 2018, my family and I made a pilgrimage to London to see the original account of Captain James Cook’s “voyage round the world” and the original Australian botanical specimens collected by Sir Joseph Banks. There were stop-offs to see Watson and Crick’s original model of DNA, fossils of early life, a Moai statue from Rapa Nui, a cross-sectional cut through a 1,500-year-old sequoia tree trunk, a statue of Charles Darwin, the Broad Street pump, Winston Churchill’s War Rooms, and the Royal Society, of course. Tracing the path of Cook along the lower east coast of Australia, or “New Holland,” as it was called then, it is obvious that Banks already had a colony in mind, one that would never forget him. Not only was the original site named Botany Bay, the coast was named “Cape Banks.” After exploring Botany Bay, the explorers’ tall ship, the HMS Endeavor, sailed north, past the heads of a harbor they called Port Jackson, which, thanks to its much deeper waters and the presence of a stream to supply fresh water, ended up being a far superior site for Governor Phillip to start a penal colony eight years later.
10. “Phillip’s Exploration of Middle Harbour Creek,” Fellowship of the First Fleeters, Arthur Phillip Chapter, http://arthurphillipchapter.weebly.com/exploration-of-middle-harbour-creek.html.
11. The Spanish explorer and conquistador’s search for the mystical spring known as the Fountain of Youth is apocryphal, but it makes for a good story. J. Greenspan, “The Myth of Ponce de León and the Fountain of Youth,” “History Stories,” April 2, 2013, A&E Television Networks, https://www.history.com/news/the-myth-of-ponce-de-leon-and-the-fountain-of-youth.
12. According to the Creation Wiki: the Encyclopedia of Creation Science (a website of the Northwest Creation Network, http://creationwiki.org/Human_longevity), in Genesis, most of us once got to 900 years, then we didn’t. Then most of us got to 400, then we didn’t. Then most of us got to 120, then we didn’t. In more recent times, as Oeppen and Vaupel have written, “Mortality experts have repeatedly asserted that life expectancy is close to an ultimate ceiling; these experts have repeatedly been proven wrong. The apparent leveling off of life expectancy in various countries is an artifact of laggards catching up and leaders falling behind.” J. Oeppen and J. W. Vaupel, “Broken Limits to Life Expectancy,” Science 296, no. 5570 (May 10, 2002): 1029–31.
13. There is some debate as to what constitutes verifiable age. There are humans who have claimed, and provided considerable evidence, of being of great age, but who don’t have formal Western-style records of their year of birth. In any case, these people are one in a billion, if that. In November 2018, the Russian gerontologist Valery Novoselov and the mathematician Nikolay Zak claimed that after much research, they believe that Jeanne Calment’s daughter, Yvonne, usurped Jeanne’s identity in 1934, claiming that the daughter had died instead of the mother to avoid paying estate taxes. The debate continues. “French Scientists Dismiss Russian Claims over Age of World’s Oldest Person,” Reuters, January 3, 2019, https://www.reuters.com/article/us-france-oldest-woman-controversy/french-scientists-dismiss-russian-claims-over-age-of-worlds-oldest-person-idUSKCN1OX145.
14. Italian researchers found after studying 4,000 elderly people that if you make it to age 105, the risk of death effectively plateaus from one birthday to the next, the odds of dying in the next year becoming approximately fifty-fifty. E. Barbi, F. Lagona, M. Marsili, et al., “The Plateau of Human Mortality: Demography of Longevity Pioneers,” Science 360, no. 396 (June 29, 2018): 1459–61, http://science.sciencemag.org/content/360/6396/1459.
15. “If people live on average to 80 or 90, like they do now, then the very long lived make it to 110 or 120,” says Siegfried Hekimi, professor of genetics at McGill University in Canada. “So if the average lifespan keeps expanding, that would mean the long-lived would live even longer, beyond 115 years”; A. Park, “There’s No Known Limit to How Long Humans Can Live, Scientists Say,” Time, June 28, 2017, http://time.com/4835763/how-long-can-humans-live/.
16. “Any sufficiently advanced technology is indistinguishable from magic.” “Arthur C. Clarke,” Wikiquote, https://en.wikiquote.org/wiki/Arthur_C._Clarke.
ONE. VIVA PRIMORDIUM
1. D. Damer and D. Deamer, “Coupled Phases and Combinatorial Selection in Fluctuating Hydrothermal Pools: A Scenario to Guide Experimental Approaches to the Origin of Cellular Life,” Life 5, no. 1 (2015): 872–87, https://www.mdpi.com/2075-1729/5/1/872.
2. According to precise radiological and geological readings and recent discoveries about the early chemistry of life, this is an accurate picture of how the inanimate was animated and life took hold. M. J. Van Kranendonk, D. W. Deamer, and T. Djokic, “Life on Earth Came from a Hot Volcanic Pool, Not the Sea, New Evidence Suggests,” Scientific American, August 2017, https://www.scientificamerican.com/article/life-on-earth-came-from-a-hot-volcanic-pool-not-the-sea-new-evidence-suggests/.
3. J. B. Iorgulescu, M. Harary, C. K. Zogg, et al., “Improved Risk-Adjusted Survival for Melanoma Brain Metastases in the Era of Checkpoint Blockade Immunotherapies: Results from a National Cohort,” Cancer Immunology Research, 6, no. 9 (September 2018): 1039–45, http://cancerimmunolres.aacrjournals.org/content/6/9/1039.long; R. L. Siegel, K. D. Miller, and A. Jemal, “Cancer Statistics, 2019,” CA: A Cancer Journal for Clinicians 69, no. 1 (January–February 2019): 7–34, https://onlinelibrary.wiley.com/doi/full/10.3322/caac.21551.
4. As far back as Aristotle, scientists and philosophers have struggled to resolve the enigma of aging, the authors wrote. D. Fabian and T. Flatt, “The Evolution of Aging,” Nature Education Knowledge 3, no. 10 (2011): 9, https://www.nature.com/scitable/knowledge/library/the-evolution-of-aging-23651151.
5. A bat from Siberia set a world record when it reached 41 years of age. R. Locke, “The Oldest Bat: Longest-Lived Mammals Offer Clues to Better Aging in Humans,” BATS Magazine 24, no. 2 (Summer 2006): 13–14, http://www.batcon.org/resources/media-education/bats-magazine/bat_article/152.
6. Small colonies of lizards on a series of Caribbean islands were likely to explore islands where there weren’t predators, while less adventurous animals survived better when predators were present. O. Lapiedra, T. W. Schoener, M. Leal, et al., “Predator-Driven Natural Selection on Risk-Taking Behavior in Anole Lizards,” Science 360, no. 3692 (June 1, 2018): 1017–20, http://science.sciencemag.org/content/360/6392/1017.
7. Richard Dawkins eloquently made this point in River Out of Eden, arguing that primitive societies don’t have a place in science, using as an example their belief the moon is an old calabash tossed into the sky. R. Dawkins, River Out of Eden (New York: Basic Books, 1995).
8. See “The Scale of Things” at the end of this book.
9. Szilard spent his last years as a fellow of the Salk Institute for Biological Studies in La Jolla, California, as a resident fellow. He lived in a bungalow on the property of the Hotel del Charro and died on May 30, 1964.
10. R. Anderson, “Ionizing Radiation and Aging: Rejuvenating an Old Idea,” Aging 1, no. 11 (November 17, 2009): 887–902, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2815743/.
11. L. E. Orgel, “The Maintenance of the Accuracy of Protein Synthesis and Its Relevance to Ageing,” Proceedings of the National Academy of Sciences of the United States of America 49, no. 4 (April 1963): 517–21, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC299893/.
12. Harman concluded that the diseases related to aging, as well as aging itself, stem fundamentally from “the deleterious side attacks of free-radicals on cell constituents and on the connective tissues.” The source of the free radicals, he continued, was “molecular oxygen catalyzed in the cell by the oxidative enzymes” and metal traces. D. Harman, “Aging: A Theory Based on Free Radical and Radiation Chemistry,” Journal of Gerontology 11, no. 3 (July 1, 1956): 298–300, https://academic.oup.com/geronj/article-abstract/11/3/298/616585?redirectedFrom=fulltext.
13. Nutraceuticals World predicts that a rising appetite for synthetic antioxidants at the same time as a fall in costs, combined with increasing demand for them by food and beverage companies, will power market growth for the next few years. “Global Antioxidants Market Expected to Reach $4.5 Billion by 2022,” Nutraceuticals World, January 26, 2017, https://www.nutraceuticalsworld.com/contents/view_breaking-news/2017-01-26/global-antioxidants-market-expected-to-reach-45-billion-by-2022
14. The sharp growth in demand for drinks with a health benefit, a beverage industry website finds, goes hand in hand with consumers wanting ingredients they value. A. Del Buono, “Consumers’ Understanding of Antioxidants Grows,” Beverage Industry, January 16, 2018, https://www.bevindustry.com/articles/90832-consumers-understanding-of-antioxidants-grows?v=preview.
15. I. Martincorena, J. C. Fowler, A. Wabik, et al., “Somatic Mutant Clones Colonize the Human Esophagus with Age,” Science 362, no. 6417 (November 23, 2018): 911–17, https://www.ncbi.nlm.nih.gov/pubmed/30337457.
16. The authors concluded that their data “calls into serious question the hypothesis that alterations in oxidative damage/stress play a role in the longevity of mice.” V. I. Pérez, A. Bokov, H. Van Remmen, et al., “Is the Oxidative Stress Theory of Aging Dead?,” Biochimica et Biophysica Acta 1790, no. 10 (October 2009): 1005–14, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2789432/.
17. A. P. Gomes, N. L. Price, A. J. Ling, et al., “Declining NAD(+) Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication During Aging,” Cell 155, no. 7 (December 19, 2013): 1624–38, https://www.ncbi.nlm.nih.gov/pubmed/24360282.
18. W. Lanouette and B. Silard, Genius in the Shadows: A Biography of Leo Szilard: The Man Behind the Bomb (New York: Skyhorse Publishing, 1992).
19. According to the NIH fact sheet, “clones created from a cell taken from an adult might have chromosomes that are already shorter than normal, which may condemn the clones’ cells to a shorter life span.” “Cloning,” National Human Genome Research Institute, March 21, 2017, https://www.genome.gov/25020028/cloning-fact-sheet/.
20. In the debates over Dolly the cloned sheep, the question that has proved to be challenging to answer is how old an animal is at birth when cloned from an adult’s cell. The answer an author on the site The Conversation found was that other clones born from the same cell as Dolly lived normal lifespans. “The new Dollies are now telling us that if we take a cell from an animal of any age, and we introduce its nucleus into a nonfertilized mature egg, we can have an individual born with its lifespan fully restored.” J. Cibell, “More Lessons from Dolly the Sheep: Is a Clone Really Born at Age Zero?,” The Conversation, February 17, 2017, https://theconversation.com/more-lessons-from-dolly-the-sheep-is-a-clone-really-born-at-age-zero-73031.
21. Though some cloned animals match their species’ rates of normal aging, it’s a field that still needs further analysis to get beyond the largely anecdotal evidence so far collected. J. P. Burgstaller and G. Brem, “Aging of Cloned Animals: A Mini-Review,” Gerontology 63, no. 5 (August 2017): 417–25, https://www.karger.com/Article/FullText/452444.
22. University of Bath researchers found in cloned mice that the telomeres protecting the ends of chromosomes were, surprisingly, slightly longer in successive generations and demonstrated no evidence of premature aging. T. Wakayama, Y. Shinkai, K. L. K. Tamashiro, et al., “Ageing: Cloning of Mice to Six Generations,” Nature 407 (September 21, 2000): 318–19. “Despite the length of telomeres reported in different studies, most clones appear to be aging normally. In fact, the first cattle clones ever produced are alive, healthy, and are 10 years old as of January 2008”; “Myths About Cloning,” U.S. Food & Drug Administration, August 29, 2018, https://www.fda.gov/animalveterinary/safetyhealth/animalcloning/ucm055512.htm.
23. The authors discovered mitochondrial DNA in a Neanderthal bone in Croatia that revealed older dates of survival than previously thought. T. Devièse, I. Karavanié, D. Comeskey, et al., “Direct Dating of Neanderthal Remains from the Site of Vindija Cave and Implications for the Middle to Upper Paleolithic Transition,” Proceedings of the National Academy of Sciences of the United States of America 114, no. 40 (October 3, 2017): 10606–11, https://www.ncbi.nlm.nih.gov/pubmed/28874524.
24. A. S. Adikesevan, “A Newborn Baby Has About 26,000,000,000 Cells. An Adult Has About 1.9 × 103 Times as Many Cells as a Baby. About How Many Cells Does an Adult Have?,” Socratic, January 26, 2017, https://socratic.org/questions/a-newborn-baby-has-about-26-000-000-000-cells-an-adult-has-about-1-9-10-3-times-.
25. C. B. Brachmann, J. M. Sherman, S. E. Devine, et al., “The SIR2 Gene Family, Conserved from Bacteria to Humans, Functions in Silencing, Cell Cycle Progression, and Chromosome Stability,” Genes & Development 9, no. 23 (December 1, 1995): 2888–902, http://genesdev.cshlp.org/content/9/23/2888.long; X. Bi, Q. Yu, J. J. Sandmeier, and S. Elizondo, “Regulation of Transcriptional Silencing in Yeast by Growth Temperature,” Journal of Molecular Biology 34, no. 4 (December 3, 2004): 893–905, https://www.ncbi.nlm.nih.gov/pubmed/15544800.
26. It is one of the most interesting and important papers I’ve ever read. C. E. Shannon, “A Mathematical Theory of Communication,” Bell System Technical Journal 27, no. 3 (July 1948): 379–423, and 27, no. 4 (October 1948): 623–66, http://math.harvard.edu/~ctm/home/text/others/shannon/entropy/entropy.pdf.
27. Research by the authors showed that mTORC1 signaling in cancer cells increases survival by “suppressing endogenous DNA damage, and may control cell fate through the regulation of CHK1.” X. Zhou, W. Liu, X. Hu, et al., “Regulation of CHK1 by mTOR Contributes to the Evasion of DNA Damage Barrier of Cancer Cells,” Nature Scientific Reports, May 8, 2017, https://www.nature.com/articles/s41598-017-01729-w; D. M. Sabatini, “Twenty-five Years of mTOR: Uncovering the Link from Nutrients to Growth,” Proceedings of the National Academy of Sciences of the United States of America 114, no. 45 (November 7, 2017): 11818–25, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5692607/.
28. E. J. Calabrese, “Hormesis: A Fundamental Concept in Biology,” Microbial Cell 1, no. 5 (May 5, 2014): 145–49, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5354598/.
TWO. THE DEMENTED PIANIST
1. Up to 69 percent of the human genome may be repetitive or derived from endogenous viral DNA repeats, compared to previous estimates of around half. A. P. de Konig, W. Gu, T. A. Castoe, et al., “Repetitive Elements May Comprise over Two-thirds of the Human Genome,” PLOS Genetics 7, no. 12 (December 7, 2011), https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3228813/.
2. Just what do we mean by the word finished when it comes to the sequencing of the human genome? Turns out, more than we thought back in the early 2000s. Regions of the genome previously thought of as nonfunctional are now emerging as playing potential roles in cancer, autism, and aging. S. Begley, “Psst, the Human Genome Was Never Completely Sequenced. Some Scientists Say It Should Be,” STAT, June 20, 2017, https://www.statnews.com/2017/06/20/human-genome-not-fully-sequenced/.
3. Dating back to the 1960s, every three or four years the center has published a catalog of its strains of Saccharomyces cerevisiae. R. K. Mortimer, “Yeast Genetic Stock Center,” Grantome, 1998, http://grantome.com/grant/NIH/P40-RR004231-10S1.
4. Yeast researchers have interesting names. John Johnston and my adviser Dick Dickinson are just two of them.
5. In 2016, Dr. Yoshinori Ohsumi won the Nobel Prize in Physiology or Medicine for his work on autophagy in yeast. That’s when cells stave off extinction during hard times by digesting nonkey parts of themselves. B. Starr, “A Nobel Prize for Work in Yeast. Again!,” Stanford University, October 3, 2016, https://www.yeastgenome.org/blog/a-nobel-prize-for-work-in-yeast-again.
6. Dawes’s delightful tour of his experiences in the world of academe and cell biology research is a refreshingly direct and personal account of a remarkable journey into yeast research over four decades. I. Dawes, “Ian Dawes—the Third Pope—Lucky to Be a Researcher,” Fems Yeast Research 6, no. 4 (June 2016), https://academic.oup.com/femsyr/article/16/4/fow040/2680350.
7. I also learned, the hard way, that I should not drink copious quantities of yeasty beer.
8. For four years after that, I sent Professor Melton a bottle of red wine for New Year’s, just to say thanks for changing my life. He never acknowledged any of them or ever smiled at me, either because he didn’t think that’s what an awardee should do or because he’s a very private person. At least he knew I was grateful. The selection of red wine turned out to be ironic, as that foodstuff helped propel my career a second time nine years later.
9. C. E. Yu, J. Oshima, Y. H. Fu, et al., “Positional Cloning of the Werner’s Syndrome Gene,” Science 27, no. 5259 (April 12, 1996): 258–62, https://www.ncbi.nlm.nih.gov/pubmed/8602509.
10. SIR2 stands for “silent information regulator 2.” When SIR2 is written in capitals and italics, it refers to the gene; when it’s written Sir2, it refers to the protein.
11. In a paper published in late 1997, I showed how ERCs—rDNA circles—cause aging and shorten the life of yeast cells. D. A. Sinclair and L. Guarente, “Extrachromosomal rDNA Circles—A Cause of Aging in Yeast,” Cell 91, no. 7 (December 26, 1997): 1033–42, https://www.ncbi.nlm.nih.gov/pubmed/9428525.
12. One way to think of the epigenome is as a cell’s software. In the same way digital files are stored in a phone’s memory and the software uses the ones and zeros to turn a phone into a clock, calendar, or music player, a cell’s information is stored as As, Ts, Gs, and Ts, and the epigenome uses those letters to direct a yeast cell to become male or a female and turn a mammalian cell into a nerve, a skin cell, or an egg.
13. I am not the first person to use this analogy. One of the earliest uses of the piano metaphor I can find came from a study guide intended to accompany a Nova ScienceNOW program on epigenetics in 2007. “Nova ScienceNOW: Epigenetics,” PBS, http://www.pbs.org/wgbh/nova/education/viewing/3411_02_nsn.html.
14. C. A. Makarewich and E. N. Olson, “Mining for Micropeptides,” Trends in Cell Biology 27, no. 9 (September 27, 2017): 685–96, https://www.ncbi.nlm.nih.gov/pubmed/28528987.
15. D. C. Dolinoy, “The Agouti Mouse Model: An Epigenetic Biosensor for Nutritional and Environmental Alterations on the Fetal Epigenome,” Nutrition Reviews 66, suppl. 1 (August 2008): S7–11, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2822875/.
16. The more extroverted you are, the longer your lifespan, while, perhaps unsurprisingly, pessimists and psychotics see significant increases in the risk of death at an earlier age. That’s according to a study of 3,752 twins 50 years or older that looked at the relationship between personality and lifespan through the prism of genetic influences. M. A. Mosing, S. E. Medland, A. McRae, et al., “Genetic Influences on Life Span and Its Relationship to Personality: A 16-Year Follow-up Study of a Sample of Aging Twins,” Psychosomatic Medicine 74, no. 1 (January 2012): 16–22, https://www.ncbi.nlm.nih.gov/pubmed/22155943. The authors considered definitions of extreme longevity, using multiple European twin registries. A. Skytthe, N. L. Pedersen, J. Kaprio, et al., “Longevity Studies in GenomEUtwin,” Twin Research 6, no. 5 (October 2003): 448–54, https://www.ncbi.nlm.nih.gov/pubmed/14624729.
17. It was a eureka moment—discovering why yeast cells age. Supercoiled circles of ribosomal DNA pinch off the yeast chromosome and accumulate as the yeast divide, distracting the Sir2 enzyme from its main role of controlling genes for sex and reproduction. David A. Sinclair and Leonard Guarente, “Extrachromosomal rDNA Circles—A Cause of Aging in Yeast,” Cell 91 (December 26, 1997): 1033–42.
18. D. A. Sinclair, K. Mills, and L. Guarente, “Accelerated Aging and Nucleolar Fragmentation in Yeast SGS1 Mutants,” Science 277, no. 5330 (August 29, 1997): 1313–16, https://www.ncbi.nlm.nih.gov/pubmed/9271578.
19. Sinclair and Guarente, “Extrachromosomal rDNA Circles—A Cause of Aging in Yeast.”
20. K. D. Mills, D. A. Sinclair, and L. Guarente, “MEC1-Dependent Redistribution of the Sir3 Silencing Protein from Telomeres to DNA Double-Strand Breaks,” Cell 97, no. 5 (May 28, 1999): 609–20, https://www.ncbi.nlm.nih.gov/pubmed/10367890.
21. Sinclair, Mills, and Guarente, “Accelerated Aging and Nucleolar Fragmentation in Yeast SGS1 Mutants.”
22. P. Oberdoerffer, S. Michan, M. McVay, et al., “SIRT1 Redistribution on Chromatin Promotes Genomic Stability but Alters Gene Expression During Aging,” Cell 135, no. 5 (November 28, 2008): 907–18, https://www.cell.com/cell/fulltext/S0092-8674(08)01317-2; Z. Mao, C. Hine, X. Tian, et al., “SIRT6 Promotes DNA Repair Under Stress by Activating PARP1,” Science 332, no. 6036 (June 2011): 1443–46, https://www.ncbi.nlm.nih.gov/pubmed/21680843.
23. A. Ianni, S. Hoelper, M. Krueger, et al., “Sirt7 Stabilizes rDNA Heterochromatin Through Recruitment of DNMT1 and Sirt1,” Biochemical and Biophysical Research Communications 492, no. 3 (October 21, 2017): 434–40, https://www.ncbi.nlm.nih.gov/m/pubmed/28842251/.
24. The authors show how SIRT7, in protecting against the instability of rDNA, also guards against the death of human cells. S. Paredes, M. Angulo-Ibanez, L. Tasselli, et al., “The Epigenetic Regulator SIRT7 Guards Against Mammalian Cellular Senescence Induced by Ribosomal DNA Instability,” Journal of Biological Chemistry 293 (July 13, 2018): 11242–50, http://www.jbc.org/content/293/28/11242.
25. Oberdoerffer et al., “SIRT1 Redistribution on Chromatin Promotes Genomic Stability but Alters Gene Expression During Aging.”
26. M. W. McBurney, X. Yang, K. Jardine, et al., “The Mammalian SIR2alpha Protein Has a Role in Embryogenesis and Gametogenesis,” Molecular and Cellular Biology 23, no. 1 (January 23, 2003): 38–54, https://mcb.asm.org/content/23/1/38.long.
27. R.-H. Wang, K. Sengupta, L. Cuiling, et al., “Impaired DNA Damage Response, Genome Instability, and Tumorigenesis in SIRT1 Mutant Mice,” Cancer Cell 14, no. 4 (October 7, 2008): 312–23, https://www.cell.com/cancer-cell/fulltext/S1535-6108(08)00294-8.
28. R. Mostoslavsky, K. F. Chua, D. B. Lombard, et al., “Genomic Instability and Aging-like Phenotype in the Absence of Mammalian SIRT6,” Cell 124 (January 27, 2006): 315–29, https://doi.org/10.1016/j.cell.2005.11.044.
29. The treatments work better in male mice, for reasons that are not yet known, but my former postdoc Haim Cohen at Bar-Ilan University in Israel wins the award for the best-ever name given to a transgenic mouse strain: MOSES. A. Satoh, C. S. Brace, N. Rensing, et al., “Sirt1 Extends Life Span and Delays Aging in Mice Through the Regulation of Nk2 Homeobox 1 in the DMH and LH,” Cell Metabolism 18, no. 3 (September 3, 2013): 416–30, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3794712.
30. When we write SIR2 in capitals and italics, it refers to the gene; when we write Sir2, it refers to the protein the gene encodes.
31. It’s possible that by not allowing mating-type genes to turn on, yeast with additional copies of SIR2 have less efficient DNA repair by homologous recombination, which is what the expression of mating-type genes also does when switched on besides preventing mating. This needs to be tested. But at least under safe lab conditions, the cells grow perfectly fine.
32. M. G. L. Baillie, A Slice Through Time: Dendrochronology and Precision Dating (London: Routledge, 1995).
33. Along with bristlecones, Matthew LaPlante, my coauthor on Lifespan, looks at a wide variety of biology’s outliers that define the very edges of our understanding of plants and animals, from ghost sharks and elephants to beetles and microbacteria. M. D. LaPlante, Superlative: The Biology of Extremes (Dallas: BenBella Books, 2019).
34. When researchers compared trees of a variety of ages to look for a steady incremental decline in annual shoot growth, they found “no statistically significant age-related differences.” R. M. Lanner, and K. F. Connor, “Does Bristlecone Pine Senesce?,” Experimental Gerontology 36, nos. 4–6 (April 2001): 675–85, https://www.sciencedirect.com/science/article/pii/S0531556500002345?via%3Dihub.
35. Investigating mutations in the gene Daf-2, researchers made a remarkable find: the largest reported lifespan extension of any living thing, namely twice as long. This relied on the involvement of two genes, Daf-2 and Daf-16, opening the door to new horizons of ways to understand how to prolong life. C. Kenyon, J. Chang, E. Gensch, et al., “A C. elegans Mutant That Lives Twice as Long as Wild Type,” Nature 366 (December 2, 1993): 461–64, https://www.nature.com/articles/366461a0; F. Wang, C.-H. Chan, K. Chen, et al., “Deacetylation of FOXO3 by SIRT1 or SIRT2 Leads to Skp2-Mediated FOXO3 Ubiquitination and Degradation,” Oncogene 31, no. 12 (March 22, 2012): 1546–57, https://www.nature.com/articles/onc2011347.
36. Why do genes often have a variety of names? The language of genetics is just like any other language; its words contain the echoes of history. Knowing the entire genome of a yeast cell, a nematode worm, or a human was the stuff of dreams less than a quarter century ago. Now, of course, I can sequence my own genome in a day on a USB drive–sized sequencer. When I was a student, genes would be given a name based on the characteristics of mutants we would generate with mutagenic chemicals. Typically, all we knew about a gene when we named it was its rough location on a particular chromosome. Only later were its distant cousins identified.
37. A. Brunet, L. B. Sweeney, J. F. Sturgill, et al., “Stress-Dependent Regulation of FOXO Transcription Factors by the SIRT1 Deacetylase,” Science 303, no. 5666 (March 24, 2004): 2011–15, https://www.ncbi.nlm.nih.gov/pubmed/14976264.
38. O. Medvedik, D. W. Lamming, K. D. Kim, and D. A. Sinclair, “MSN2 and MSN4 Link Calorie Restriction and TOR to Sirtuin-Mediated Lifespan Extension in Saccharomyces cerevisiae,” PLOS Biology, October 2, 2007, http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.0050261.
39. The authors found convincing evidence linking FOXO3 and longevity in humans. L. Sun, C. Hu, C. Zheng, et al., “FOXO3 Variants Are Beneficial for Longevity in Southern Chinese Living in the Red River Basin: A Case-Control Study and Meta-analysis,” Nature Scientific Reports, April 27, 2015, https://www.nature.com/articles/srep09852.
40. H. Bae, A. Gurinovich, A. Malovini, et al., “Effects of FOXO3 Polymorphisms on Survival to Extreme Longevity in Four Centenarian Studies,” Journals of Gerontology, Series A: Biological Sciences and Medical Sciences 73, no. 11 (October 8, 2018): 1437–47, https://academic.oup.com/biomedgerontology/article/73/11/1439/3872296.
41. If you’re a dedicated exerciser in middle age or an athlete in her fifties, chances are your heart is going to resemble that of someone much younger, several studies have revealed. Not so for the office worker who doesn’t exercise or someone who hits the gym or runs in the street on a sporadic basis. What isn’t clear, though, is whether commencing an aggressive exercise program in your middle years can turn around the effects of a sedentary lifestyle on the heart’s functioning and structure. G. Reynolds, “Exercise Makes the Aging Heart More Youthful,” New York Times, July 25, 2018, https://www.nytimes.com/2018/07/25/well/exercise-makes-the-aging-heart-more-youthful.html.
42. “These findings have implications for improving blood flow to organs and tissues, increasing human performance, and reestablishing a virtuous cycle of mobility in the elderly.”A. Das, G. X. Huang, M. S. Bonkowski, et al., “Impairment of an Endothelial NAD+-H2S Signaling Network Is a Reversible Cause of Vascular Aging,” Cell 173, no. 1 (March 22, 2018): 74–89, https://www.cell.com/cell/pdf/S0092-8674(18)30152-1.pdf.
1. F. Bacon, Of the Proficience and Advancement of Learning, Divine and Human (Oxford, UK: Leon Lichfield, 1605). An original of this book sits on our mantelpiece at home, a gift from Sandra, my wife.
2. C. Kenyon, J. Chang, E. Gensch, et al., “A C. elegans Mutant That Lives Twice as Long as Wild Type,” Nature 366, no. 6454 (December 2, 1993): 461–64, https://www.nature.com/articles/366461a0.
3. L. Partridge and P. H. Harvey, “Methuselah Among Nematodes,” Nature 366, no. 6454 (December 2, 1993): 404–5, https://www.ncbi.nlm.nih.gov/pubmed/8247143.
4. “Decelerated aging,” Gems wrote, “has an element of tragic inevitability: its benefits to health compel us to pursue it, despite the transformation of human society, and even human nature, that this could entail.” D. Gems, “Tragedy and Delight: The Ethics of Decelerated Ageing,” Philosophical Transactions of the Royal Society B: Biological Sciences 366 (January 12, 2011): 108–12, https://royalsocietypublishing.org/doi/pdf/10.1098/rstb.2010.0288.
5. “You know the cartoon where Bugs Bunny is driving an old car that suddenly falls apart, every bolt sprung, with the last hubcap rattling in a circle until it comes to rest?” Washington Post reporter David Brown wrote in 2010. “Some people die like that, too. The trouble is there’s not a good name for it.” D. Brown, “Is It Time to Bring Back ‘Old Age’ as a Cause of Death?” Washington Post, September 17, 2010, http://www.washingtonpost.com/wp-dyn/content/article/2010/09/17/AR2010091703823.html?sid=ST2010091705724.
6. “Really, people don’t die of old age,” Chris Weller wrote on Medical Daily. “Something else has to be going on.” C. Weller, “Can People Really Die of Old Age?,” “The Unexamined Life,” Medical Daily, January 21, 2015, http://www.medicaldaily.com/can-people-really-die-old-age-318528.
7. B. Gompertz, “On the Nature of the Function Expressive of the Law of Human Mortality, and on a New Mode of Determining the Value of Life Contingencies,” Philosophical Transactions of the Royal Society 115 (January 1, 1825): 513–85, https://royalsocietypublishing.org/doi/10.1098/rstl.1825.0026.
8. D. A. Sinclair and L. Guarente, “Extrachromosomal rDNA Circles—A Cause of Aging in Yeast,” Cell 91, no. 7 (December 26, 1997): 1033–42, https://www.ncbi.nlm.nih.gov/pubmed/9428525.
9. Based on global population estimates and census reports, among other sources, the World Bank plotted out a fifty-six-year period ending in 2016 that showed life expectancy increasing from 52 to 72. “Life Expectancy at Birth, Total (Years),” The World Bank, https://data.worldbank.org/indicator/SP.DYN.LE00.IN.
10. I inherited the SERPINA1 mutation from my mother. Even though I have never smoked, I find it hard to breathe in some situations, such as when I am visiting a place with substantial pollution. Armed with this information, I avoid breathing in dust and other contaminants when possible. I feel empowered knowing the genetic instructions within each of my cells, an experience that previous generations never had.
11. A. M. Binder, C. Corvalan, V. Mericq, et al., “Faster Ticking Rate of the Epigenetic Clock Is Associated with Faster Pubertal Development in Girls,” Epigenetics 13, no. 1 (February 15, 2018): 85–94, https://www.tandfonline.com/doi/full/10.1080/15592294.2017.1414127.
12. Women over 65 are more prone to hip fractures, with sepsis being the main cause of death. Researchers have linked the sepsis to poor medical care, a lack of family support, and dementia. “Time wise, mortality was found to be higher within the first six months, with 10 deaths (50%), and within the first year, with six deaths (30%).” J. Negrete-Corona, J. C. Alvarano-Soriano, and L. A. Reyes-Santiago, “Hip Fracture as Risk Factor for Mortality in Patients over 65 Years of Age. Case-Control Study” (abstract translation from Spanish), Acta Ortopédica Mexicana 28, no. 6 (November–December 2014): 352–62, https://www.ncbi.nlm.nih.gov/pubmed/26016287, (Spanish) http://www.medigraphic.com/pdfs/ortope/or-2014/or146c.pdf.
13. Up to 74 percent of patients who have a foot amputated due to diabetes die within five years of surgery. The authors argue for more aggressive focus on the issue by doctors and patients alike. “New-onset diabetic foot ulcers should be considered a marker for significantly increased mortality and should be aggressively managed locally, systemically, and psychologically.”J. M. Robbins, G. Strauss, D. Aron, et al., “Mortality Rates and Diabetic Foot Ulcers: Is It Time to Communicate Mortality Risk to Patients with Diabetic Foot Ulceration?,” Journal of the American Podiatric Medical Association 98, no. 6 (November–December 2008): 489–93, https://www.ncbi.nlm.nih.gov/pubmed/19017860.
14. Have we made a deal with the medical devil that’s backfired? Olshansky certainly thinks so, contrasting the quest for human longevity and health to the dark narrative of Faust’s ultimately pyrrhic deal with Mephistopheles. “It’s possible that humanity has squeezed about as much healthy life out of public health interventions as possible and that the human body is now running up against inherent limits that the genetically fixed attributes of our biology impose.” S. J. Olshansky, “The Future of Health,” Journal of the American Geriatrics Society 66, no. 1 (December 5, 2017): 195–97, https://onlinelibrary.wiley.com/doi/full/10.1111/jgs.15167.
15. The numbers are indeed staggering: close to 800,000 Americans die annually of cardiovascular-related diseases; medical costs related to cardiovascular issues are expected to be over $818 billion by 2030 and lost productivity costs above $275 billion. “Heart Disease and Stroke Cost America Nearly $1 Billion a Day in Medical Costs, Lost Productivity,” CDC Foundation, April 29, 2015, https://www.cdcfoundation.org/pr/2015/heart-disease-and-stroke-cost-america-nearly-1-billion-day-medical-costs-lost-productivity.
16. As treatments for patients with disease have prolonged their lives, so the amount of disease in society has augmented. This situation means that the only way to increase the human healthspan will be by “ ‘delaying aging,’ or delaying the physiological change that results in disease and disability,” the author argues. Along with scientific breakthroughs, changes in socioeconomic inequalities, lifestyle, and behavior can contribute to improving both healthspan and lifespan. E. M. Crimmins, “Lifespan and Healthspan: Past, Present, and Promise,” Gerontologist 55, no. 6 (December 2015): 901–11, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4861644/.
17. According to the World Health Organization, one DALY can be thought of as one lost year of “healthy” life. The sum of these DALYs across the population, or the burden of disease, can be thought of as a measurement of the gap between current health status and an ideal health situation in which the entire population lives to an advanced age, free of disease and disability. “Metrics: Disability-Adjusted Life Year (DALY),” World Health Organization, https://www.who.int/healthinfo/global_burden_disease/metrics_daly/en/.
18. And almost everyone at that age spends a considerable part of his or her life visiting the doctor. According to the study, published in 2009 by the British Medical Journal, 94 percent of 85-year-olds had had contact with a doctor in the past year, and one in ten was in institutional care. J. Collerton, K. Davies, C. Jagger, et al., “Health and Disease in 85 Year Olds: Baseline Findings from the Newcastle 85+ Cohort Study,” British Medical Journal, December 23, 2009, https://www.bmj.com/content/339/bmj.b4904.
19. The possibility that both genetic and epigenetic aging are needed for a tumor to develop we’ve termed “geroncogenesis,” and it explains why tumors don’t occur in young people even after extreme sun exposure, why it often takes decades for DNA damage to lead to a tumor even if you avoid the sun later in life, and why cancers often have an unusual metabolism (named after the physicist Otto Warburg), one that directly consumes glucose, has decreased mitochondrial activity, and uses less oxygen to make energy, similar to the metabolism of old cells.
20. According to the World Health Organization, “The State of Global Tobacco Control,” 2008, http://www.who.int/tobacco/mpower/mpower_report_global_control_2008.pdf.
21. R. A. Miller, “Extending Life: Scientific Prospects and Political Obstacles,” Milbank Quarterly 80, no. 1 (March 2002): 155–74, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2690099/; graph redrawn from D. L. Hoyert, K. D. Kochanek, and S. L. Murphy, “Deaths: Final Data for 1997,” National Vital Statistics Report 47, no. 19 (June 30, 1999):1–104, https://www.ncbi.nlm.nih.gov/pubmed/10410536.
22. Using a survey of 593 people that was then repeated four years later, the authors explored the role of “subjective age” (meaning how old an individual feels in contrast to his or her biological age) in shaping the process of aging. A. E. Kornadt, T. M. Hess, P. Voss, and K. Rothermund, “Subjective Age Across the Life Span: A Differentiated, Longitudinal Approach,” Journals of Gerontology: Psychological Sciences 73, no. 5 (June 1, 2018): 767–77, http://europepmc.org/abstract/med/27334638.
23. “David A. Sinclair’s Past and Present Advisory Roles, Board Positions, Funding Sources, Licensed Inventions, Investments, Funding, and Invited Talks,” Sinclair Lab, Harvard Medical School, November 15, 2018, https://genetics.med.harvard.edu/sinclair-test/people/sinclair-other.php.
FOUR. LONGEVITY NOW
1. It seems likely that he had sex at least once again, as he had one daughter, Clara, with his wife, Veronica. L. Cornaro, Sure and Certain Methods of Attaining a Long and Healthful Life: With Means of Correcting a Bad Constitution, &c., https://babel.hathitrust.org/cgi/pt?id=dul1.ark:/13960/t0dv2fm86;view=1up;seq=1.
2. There are other translations. This comes from the edition published in Milwaukee by William F. Butler in 1903.
3. A 3-year-old rat measured in terms of human lifespan would be akin to a 90-year-old human, according to a researcher quoted by the authors. One of their rats, raised on an experimental diet from 6 weeks of age, lived to 40 months, while of those rats raised on a normal diet, the oldest reached 34 months, with “less than a third of the rats in our colony . . . expected to live to be more than two years old.” T. B. Osborne, L. B. Mendel, and E. L. Ferry, “The Effect of Retardation of Growth upon the Breeding Period and Duration of Life of Rats,” Science 45, no. 1160 (March 23, 1917): 294–95, http://science.sciencemag.org/content/45/1160/294.
4. I. Bjedov, J. M. Toivonen, F. Kerr, et al., “Mechanisms of Life Span Extension by Rapamycin in the Fruit Fly Drosophila melanogaster,” Cell Metabolism 11, no. 1 (January 6, 2010): 35–46, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2824086/.
5. Among Kagawa’s findings on the impact of Western diets on the Japanese were significant increases in colon and lung cancer and decreases in stomach and uterine cancers, although the subjects’ food consumption was still much smaller than that of Americans or Europeans. When he looked at the residents of Okinawa, they had “the lowest total energy, sugar and salt, and the smallest physique, but had healthy longevity and the highest centenarian rate.” Y. Kagawa, “Impact of Westernization on the Nutrition of Japanese: Changes in Physique, Cancer, Longevity and Centenarians,” Preventive Medicine 7, no. 2 (June 1978): 205–17, https://www.sciencedirect.com/science/article/pii/0091743578902463.
6. Two of the authors of the report were themselves part of the crew who elected to be locked up inside the Biosphere for two years and live on a low-calorie diet, with just 12 percent protein and 11 percent fat in terms of calorie consumption. Despite this calorie restriction and a 17±5 percent weight loss, all eight crew members were healthy and highly active during the two-year period. R. L. Walford, D. Mock, R. Verdery, and T. MacCallum, “Calorie Restriction in Biosphere 2: Alterations in Physiologic, Hematologic, Hormonal, and Biochemical Parameters in Humans Restricted for a 2-Year Period,” Journals of Gerontology, Series A: Biological Sciences and Medical Sciences 57, no. 6 (June 2002): 211–24, https://www.ncbi.nlm.nih.gov/pubmed/12023257.
7. L. K. Heilbronn, and E. Ravussin, “Calorie Restriction and Aging: Review of the Literature and Implications for Studies in Humans,” American Journal of Clinical Nutrition 3, no. 178 (September 2003): 361–69, https://academic.oup.com/ajcn/article/78/3/361/4689958.
8. The authors used the results of a publicly accessible, 24-month trial run by the National Institute on Aging of calorie restriction in nonobese youth. D. W. Belsky, K. M. Huffman, C. F. Pieper, et al., “Change in the Rate of Biological Aging in Response to Caloric Restriction: CALERIE Biobank Analysis,” Journals of Gerontology, Series A: Biological Sciences and Medical Sciences 73, no. 1 (January 2018): 4–10, https://academic.oup.com/biomedgerontology/article/73/1/4/3834057.
9. McGlothin wrote in an article, “I am delighted that a 70-year-old can have biomarkers that are like those of a healthy school-age child.” P. McGlothin, “Growing Older and Healthier the CR Way®,” Life Extension Magazine, September 2018, https://www.lifeextension.com/Magazine/2018/9/Calorie-Restriction-Update/Page-01.
10. The authors are in no doubt of the potential benefits calorie restriction offers humans in terms of addressing diseases and aging. “A clear understanding of the biology of ageing, as opposed to the biology of individual age-related diseases, could be the critical turning point for novel approaches in preventative strategies to facilitate healthy human ageing,” they wrote. “Caloric restriction (CR) offers a powerful paradigm to uncover the cellular and molecular basis for the age-related increase in overall disease vulnerability that is shared by all mammalian species.” J. A. Mattison, R. J. Colman, T. M. Beasley, et al., “Caloric Restriction Improves Health and Survival of Rhesus Monkeys,” Nature Communications, January 17, 2017, https://www.nature.com/articles/ncomms14063.
11. Y. Zhang, A. Bokov, J. Gelfond, et al., “Rapamycin Extends Life and Health in C57BL/6 Mice,” Journals of Gerontology, Series A: Biological Sciences and Medical Sciences 69, no. 2 (February 2014): 119–30, https://www.ncbi.nlm.nih.gov/pubmed/23682161.
12. “We really study this as a paradigm to understand aging,” she told Scientific American in 2017. “We’re not recommending people do it.” R. Conniff, “The Hunger Gains: Extreme Calorie-Restriction Diet Shows Anti-aging Results,” Scientific American, February 16, 2017, https://www.scientificamerican.com/article/the-hunger-gains-extreme-calorie-restriction-diet-shows-anti-aging-results/.
13. “The optimum amount of fasting appeared to be fasting 1 day in 3 and this increased the life span of littermate males about 20% and littermate females about 15%.” A. J. Carlson and F. Hoelzel, “Apparent Prolongation of the Life Span of Rats by Intermittent Fasting: One Figure,” Journal of Nutrition 31, no. 3 (March 1, 1946): 363–75, https://academic.oup.com/jn/article-abstract/31/3/363/4725632?redirectedFrom=fulltext.
14. H. M. Shelton, “The Science and Fine Art of Fasting,” in The Hygienic System, vol. III, Fasting and Sunbathing (San Antonio, Texas: Dr. Shelton’s Health School, 1934).
15. C. Tazearslan, J. Huang, N. Barzilai, and Y. Suh, “Impaired IGF1R Signaling in Cells Expressing Longevity-Associated Human IGF1R Alleles,” Aging Cell 10, no. 3 (June 2011): 551–54, https://onlinelibrary.wiley.com/doi/full/10.1111/j.1474-9726.2011.00697.
16. One in three Ikarians reaches the age of 90, and most do so free of dementia and many other chronic diseases of aging. “Ikaria, Greece. The Island where People Forget to Die,” Blue Zones, https://www.bluezones.com/exploration/ikaria-greece/.
17. The fasting extends to 180 days in the year and requires abstinence from primarily dairy products and red-blooded animals and fish, which means that octopus and squid can still be eaten. In the run-up to Holy Communion, fasting encompasses all food. N. Gaifyllia, “Greek Orthodox 2018 Calendar of Holidays and Fasts,” The Spruce Eats, October 6, 2018, https://www.thespruceeats.com/greek-orthodox-calendar-1706215.
18. Bapan has been widely ignored by Western researchers, mostly because people in that part of southern China—a region long reputed to have large populations of very healthy centenarians—don’t have formal birth records. The cardiologist John Day and his colleagues, however, have argued that there is good reason to believe their claims. J. D. Day, J. A. Day, and M. LaPlante, The Longevity Plan: Seven Life-Transforming Lessons from Ancient China (New York: HarperCollins, 2017).
19. Avoiding animal protein is not easy. One of the main reasons is that protein consumption produces satiety. No one has done more to understand why eating carbohydrates doesn’t stave off hunger than Stephen Simpson, the director of the Charles Perkins Centre in Sydney, Australia. Simpson started his career trying to understand why locusts swarm. If he could figure that out, he felt, perhaps he could prevent the global loss of millions of tons of crops each year. What he discovered was that locusts seek protein. They crave it. They march along consuming anything edible in their path, but if there’s not enough protein in their diet, they transform into ravenous, hungry creatures that seek protein from any possible source. And the closest source of protein is the locust in front of it. Under these conditions, the best way to stay alive is to keep moving forward, occasionally pausing to snack on a slower relative. Simpson’s latest work is fascinating: it shows that this same trigger exists in the mammalian brain. When we lack protein, we also turn ravenous, and although we don’t normally try to eat our neighbors, in the throes of extreme hunger, who hasn’t considered it? What this all tells us is that it’s best not to eat a lot of animal protein, but it’s hard to avoid it altogether. F. P. Zanotto, D. Raubenheimer, and S. J. Simpson, “Selective Egestion of Lysine by Locusts Fed Nutritionally Unbalanced Foods,” Journal of Insect Physiology 40, no. 3 (March 1994): 259–65, https://www.sciencedirect.com/science/article/pii/0022191094900493.
20. Though it seems the occasional hot dog or hamburger is acceptable, a review of 800 studies by twenty-two experts found that a daily diet that included 50 grams of processed meat appeared to increase subjects’ chances of developing colorectal cancer by 18 percent. S. Simon, “World Health Organization Says Processed Meat Causes Cancer,” American Cancer Society, October 26, 2015, https://www.cancer.org/latest-news/world-health-organization-says-processed-meat-causes-cancer.html.
21. With processed, calorie-rich food largely absent from their diet and a lifestyle dominated by physical activity, there’s little in the way of obesity or cardiovascular disease to be found in hunter-gatherer communities. H. Pontzer, B. M. Wood, and D. A. Raichlen, “Hunter-Gatherers as Models in Public Health,” Obesity Reviews 19, suppl. 1 (December 2018): 24–35, https://onlinelibrary.wiley.com/doi/full/10.1111/obr.12785.
22. M. Song, T. T. Fung, F. B. Hu, et al., “Association of Animal and Plant Protein Intake with All-Cause and Cause-Specific Mortality,” JAMA Internal Medicine 176, no. 10 (October 1, 2016): 1453–63, https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2540540.
23. A 2011 study identified a new signaling pathway used by amino acids to activate mTOR. I. Tato, R. Bartrons, F. Ventura, and J. L. Rosa, “Amino Acids Activate Mammalian Target of Rapamycin Complex 2 (mTORC2) via PI3K/Akt Signaling,” Journal of Biological Chemistry 286, no. 8 (February 25, 2011): 6128–42, http://www.jbc.org/content/286/8/6128.full.
24. C. Hine, C. Mitchell, and J. R. Mitchell, “Calorie Restriction and Methionine Restriction in Control of Endogenous Hydrogen Sulfide Production by the Transsulfuration Pathway,” Experimental Gerontology 68 (August 2015): 26–32, https://www.ncbi.nlm.nih.gov/pubmed/25523462.
25. Rather than caloric restriction, the researchers at the Lamming Lab devised a short-term methionine deprivation regimen that reduced fat mass, restored normal body weight, and reinstituted glycemic control to male and female mice alike. D. Yu, S. E. Yang, B. R. Miller, et al., “Short-Term Methionine Deprivation Improves Metabolic Health via Sexually Dimorphic, mTORC1-Independent Mechanisms,” FASEB Journal 32, no. 6 (June 2018): 3471–82, https://www.ncbi.nlm.nih.gov/pubmed/29401631.
26. The eternal quest for a well-balanced diet, the answer, the authors suggest, may have to do with how “longevity can be extended in ad libitum–fed animals by manipulating the ratio of macronutrients to inhibit mTOR activation.” S. M. Solon-Biet, A. C. McMahon, J. W. Ballard, et al., “The Ratio of Macronutrients, Not Caloric Intake, Dictates Cardiometabolic Health, Aging, and Longevity in Ad Libitum–Fed Mice,” Cell Metabolism 3, no. 19 (March 4, 2014): 418–30, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5087279/.
27. In other words, the specific amino acid composition of a person’s diet may be more important than limiting all aminos. The easiest way to do this, though, is still to reduce meat intake. L. Fontana, N. E. Cummings, S. I. Arriola Apelo, et al., “Decreased Consumption of Branched Chain Amino Acids Improves Metabolic Health,” Cell Reports 16, no. 2 (July 12, 2016): 520–30, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4947548/.
28. Some have suggested that a better understanding of this connection could help researchers develop mTOR-targeted therapies to prevent muscle wasting. M.-S. Yoon, “mTOR as a Key Regulator in Maintaining Skeletal Muscle Mass,” Frontiers in Physiology 8 (2017): (October 17, 2017): 788, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5650960/.
29. Just cutting one’s consumption of branched-chain amino acids for one day rapidly improves insulin sensitivity. F. Xiao, J. Yu, Y. Guo, et al., “Effects of Individual Branched-Chain Amino Acids Ceprivation on Insulin Sensitivity and Glucose Metabolism in Mice,” Metabolism 63, no. 6 (June 2014): 841–50, https://www.ncbi.nlm.nih.gov/pubmed/24684822/.
30. There are certainly other lifestyle factors at play. But a meta-analysis of seven studies including nearly 125,000 participants, published in 2012 in Annals of Nutrition and Metabolism, is compelling evidence. Among vegetarians, the researchers who conducted the study observed a 16 percent lower mortality from circulatory diseases and a 12 percent lower mortality from cerebrovascular disease. T. Huang, B. Yang, J. Zheng, et al., “Cardiovascular Disease Mortality and Cancer Incidence in Vegetarians: A Meta-analysis and Systematic Review,” Annals of Nutrition & Metabolism 4, no. 60 (June 1, 2012): 233–40, https://www.karger.com/Article/FullText/337301.
31. The study looked at nearly 6,000 men and women enrolled in the National Health and Nutrition Examination Survey. If you want a reminder of how little a sedentary life does for prolonging existence, the following jumps out of the report: “Adults with High activity were estimated to have a biologic aging advantage of 9 years (140 base pairs ÷ 15.6) over Sedentary adults. The difference in cell aging between those with High and Low activity was also significant, 8.8 years, as was the difference between those with High and Moderate PA (7.1 years).” L. A. Tucker, “Physical Activity and Telomere Length in U.S. Men and Women: An NHANES Investigation,” Preventive Medicine 100 (July 2017): 145–51, https://www.sciencedirect.com/science/article/pii/S0091743517301470.
32. Intrigued by the potential insights into aging afforded by the health and physicality of middle-aged, regular bike riders, British scientists, among whose ranks were recreational athletes, looked at how exercise might influence longevity. They recruited older male and female cyclists between 55 and 79 for their study and contrasted them to older and younger sedentary people. “The cyclists proved to have reflexes, memories, balance and metabolic profiles that more closely resembled those of 30-year-olds than of the sedentary older group.” G. Reynolds, “How Exercise Can Keep Aging Muscles and Immune Systems ‘Young,’ ” New York Times, March 14, 2018, https://www.nytimes.com/2018/03/14/well/move/how-exercise-can-keep-aging-muscles-and-immune-systems-young.html.
33. D. Lee, R. R. Pate, C. J. Lavie, et al., “Leisure-Time Running Reduces All-Cause and Cardiovascular Mortality Risk,” Journal of the American College of Cardiology 54, no. 5 (August 2014): 472–81, http://www.onlinejacc.org/content/64/5/472.
34. The authors show how cardiorespiratory fitness algorithms can identify those at risk of cardiovascular disease and also potentially help to develop appropriate exercise regimes depending on an individual’s initial fitness level. E. G. Artero, A. S. Jackson, X. Sui, et al., “Longitudinal Algorithms to Estimate Cardiorespiratory Fitness: Associations with Nonfatal Cardiovascular Disease and Disease-Specific Mortality,” Journal of the American College of Cardiology 63, no. 21 (June 3, 2014): 2289–96, https://www.sciencedirect.com/science/article/pii/S0735109714016301?via%3Dihub.
35. T. S. Church, C. P. Earnest, J. S. Skinner, and S. N. Blair, “Effects of Different Doses of Physical Activity on Cardiorespiratory Fitness Among Sedentary, Overweight or Obese Postmenopausal Women with Elevated Blood Pressure: A Randomized Controlled Trial,” Journal of the American Medical Association 297, no. 19 (May 16, 2007): 2081–91, https://jamanetwork.com/journals/jama/fullarticle/1108370.
36. M. M. Robinson, S. Dasari, A. R. Konopka, et al., “Enhanced Protein Translation Underlies Improved Metabolic and Physical Adaptations to Different Exercise Training Modes in Young and Old Humans,” Cell Metabolism 25, no. 3 (March 7, 2017): 581–92, https://www.cell.com/cell-metabolism/comments/S1550-4131(17)30099-2.
37. Sage recommendations from the Mayo Clinic include dedicating 150 minutes a week to activities such as swimming or mowing the lawn or doing 75 minutes of more demanding exercise, such as spinning or running. “Be realistic and don’t push yourself too hard, too fast,” the clinic staff wrote. “Fitness is a lifetime commitment, not a sprint to a finish line,” “Exercise Intensity: How to Measure It,” Mayo Clinic, June 12, 2018, https://www.mayoclinic.org/healthy-lifestyle/fitness/in-depth/exercise-intensity/art-20046887.
38. Investigating how the hypothalamus potentially controls aspects of aging, the authors found that “immune inhibition or GnRH restoration in the hypothalamus/brain” offers two possible directions for extending lifespan and fighting health issues that come with aging. G. Zhang, J. Li, S. Purkayasatha, et al., “Hypothalamic Programming of Systemic Ageing Involving IKK-β, NF-ĸB and GnRH,” Nature 497, no. 7448 (May 9, 2013): 211–16, https://www.nature.com/articles/nature12143.
39. The team couldn’t say why this happened, only that it happened. Back then they theorized that lowering the mice’s body temperature might slow down metabolism and thus reduce the notorious free radicals. We’ve learned a lot since then. B. Conti, M. Sanchez-Alvarez, R. Winskey-Sommerer, et al., “Transgenic Mice with a Reduced Core Body Temperature Have an Increased Life Span,” Science 314, no. 5800 (November 3, 2006): 825–28, https://www.ncbi.nlm.nih.gov/pubmed/17082459.
40. The mice suffered from increased rates of obesity, beta cell dysfunction, and type 2 diabetes. C.- Y. Zhang, G. Baffy, P. Perret, et al., “Uncoupling Protein-2 Negatively Regulates Insulin Secretion and Is a Major Link Between Obesity, β Cell Dysfunction, and Type 2 Diabetes,” Cell 105, no. 6 (June 15, 2001): 745–55, https://www.sciencedirect.com/science/article/pii/S0092867401003786.
41. The researchers also believed this occurred because of a reduction in oxidative damage. Y.-W. C. Fridell, A. Sánchez-Blanco, B. A. Silvia, et al., “Targeted Expression of the Human Uncoupling Protein 2 (hUCP2) to Adult Neurons Extends Life Span in the Fly,” Cell Metabolism 1, no. 2 (February 2005): 145–52, https://www.sciencedirect.com/science/article/pii/S155041310500032X.
42. The researchers concluded that UCP2 regulates brown adipose tissue thermogenesis through nonesterified fatty acids. A. Caron, S. M. Labbé, S. Carter, et al., “Loss of UCP2 Impairs Cold-Induced Non-shivering Thermogenesis by Promoting a Shift Toward Glucose Utilization in Brown Adipose Tissue,” Biochimie 134 (March 2007): 118–26, https://www.sciencedirect.com/science/article/pii/S030090841630270X?via%3Dihub.
43. The researchers, led by Justin Darcy at the University of Alabama, demonstrated enhanced brown adipose tissue function in animals that lived 40 to 60 percent longer than their littermates. J. Darcy, M. McFadden, Y. Fang, et al., “Brown Adipose Tissue Function Is Enhanced in Long-Lived, Male Ames Dwarf Mice,” Endocrinology 157, no. 12 (December 1, 2016): 4744–53, https://academic.oup.com/endo/article/157/12/4744/2758430.
44. “How brown fat is regulated in humans and how it relates to metabolism, though, remain unclear,” the authors of a study wrote in 2014. Since then the mechanism has become clearer. Endocrine Society, “Cold Exposure Stimulates Beneficial Brown Fat Growth,” Science Daily, June 23, 2014, https://www.sciencedaily.com/releases/2014/06/140623091949.htm.
45. T. Shi, F. Wang, E. Stieren, and Q. Tong, “SIRT3, a Mitochondrial Sirtuin Deacetylase, Regulates Mitochondrial Function and Thermogenesis in Brown Adipocytes,” Journal of Biological Chemistry 280, no. 14 (April 8, 2005): 13560-67, http://www.jbc.org/content/280/14/13560.long.
46. A. S. Warthin, “A Fatal Case of Toxic Jaundice Caused by Dinitrophenol,” Bulletin of the International Association of Medical Museums 7 (1918): 123–26.
47. W. C. Cutting, H. G. Mertrens, and M. L. Tainter, “Actions and Uses of Dinitrophenol: Promising Metabolic Applications,” Journal of the American Medical Association 101, no. 3 (July 15, 1933): 193–95, https://jamanetwork.com/journals/jama/article-abstract/244026.
48. The authors calculated that with 1.2 million capsules supplied by the Stanford Clinics in 1934, that corresponded to 4,500 patients taking the drug over a three-month period. Overall, they estimated that in the United States, at least 100,000 people had been treated with the drug. M. L. Tainter, W. C. Cutting, and A. B. Stockton, “Use of Dinitrophenol in Nutritional Disorders: A Critical Survey of Clinical Results,” American Journal of Public Health 24, no. 10 (1935): 1045–53, https://ajph.aphapublications.org/doi/pdf/10.2105/AJPH.24.10.1045.
49. Dinitrophenol has a variety of names on the internet. The authors list, along with DNP, “ ‘Dinosan,’ ‘Dnoc,’ ‘Solfo Black,’ ‘Nitrophen,’ ‘Alidfen,’ and ‘Chemox.’ ” In the 2000s, there was a spike in DNP-related deaths as it was marketed online to bodybuilders and the weight conscious. J. Grundlingh, P. I. Dargan, M. El-Zanfaly, and D. M. Wood, “2,4-Dinitrophenol (DNP): A Weight Loss Agent with Significant Acute Toxicity and Risk of Death,” Journal of Medical Toxicology 7, no. 3 (September 2011): 205–12, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3550200/.
50. T. L. Kurt, R. Anderson, C. Petty, et al., “Dinitrophenol in Weight Loss: The Poison Center and Public Health Safety,” Veterinary and Human Toxicology 28, no. 6 (December 1986): 574–75, https://www.ncbi.nlm.nih.gov/pubmed/3788046.
51. A horrifying death from an overdose of DNP is described in a story on Vice; see G. Haynes, “The Killer Weight Loss Drug DNP Is Still Claiming Young Lives,” Vice, August 6, 2018, https://www.vice.com/en_uk/article/bjbyw5/the-killer-weight-loss-drug-dnp-is-still-claiming-young-lives; see also Grundlingh et al., “2,4-Dinitrophenol (DNP).”
52. This happens differently from species to species, but the general trend is clear: cold and exercise together build brown fat. F. J. May, L. A. Baer, A. C. Lehnig, et al., “Lipidomic Adaptations in White and Brown Adipose Tissue in Response to Exercise Demonstrates Molecular Species-Specific Remodeling,” Cell Reports 18, no. 6 (February 7, 2017): 1558–72, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5558157/.
53. “Until further research is available,” an international team of researchers concluded in 2014, “athletes should remain cognizant that less expensive modes of cryotherapy, such as local ice-pack application or cold-water immersion, offer comparable physiological and clinical effects.” C. M. Bleakley, F. Bieuzen, G. W. Davison, and J. T. Costello, “Whole-Body Cryotherapy: Empirical Evidence and Theoretical Perspectives,” Open Access Journal of Sports Medicine 5 (March 10, 2014): 25–36, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3956737/.
54. The average time spent in the sauna was 15 minutes at 80°C. T. E. Strandberg, A. Strandberg, K. Pitkälä, and A. Benetos, “Sauna Bathing, Health, and Quality of Life Among Octogenarian Men: The Helsinki Businessmen Study,” Aging Clinical and Experimental Research 30, no. 9 (September 2018): 1053–57, https://www.ncbi.nlm.nih.gov/pubmed/29188579.
55. T. Laukkanen, H. Khan, F. Zaccardi, and J. A. Laukkanen, “Association Between Sauna Bathing and Fatal Cardiovascular and All-Cause Mortality Events,” JAMA Internal Medicine 175, no. 4 (April 2015): 542–48, https://www.ncbi.nlm.nih.gov/pubmed/25705824.
56. H. Yang, T. Yang, J. A. Baur, et al., “Nutrient-Sensitive Mitochondrial NAD+ Levels Dictate Cell Survival,” Cell 130, no. 6 (September 21, 2007): 1095–107, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3366687/.
57. R. Madabhushi, F. Gao, A. R. Pfenning, et al., “Activity-Induced DNA Breaks Govern the Expression of Neuronal Early-Response Genes,” Cell 161, no. 7 (June 18, 2015): 1592–605, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4886855/.
58. H. Katoka, “Quantitation of Amino Acids and Amines by Chromatography,” Journal of Chromatography Library 70 (2005): 364–404, https://www.sciencedirect.com/topics/chemistry/aromatic-amine.
59. Another highly prevalent chemical used in plastic bottles and food and drink cans is bisphenol A, or BPA. It’s so ubiquitous that it can be found in the urine of nearly every American; in high quantities it has been linked to “cardiovascular disease and diabetes and may be associated with an increased risk for miscarriages with abnormal embryonic karyotype.” P. Allard and M. P. Colaiácovo, “Bisphenol A Impairs the Double-Strand Break Repair Machinery in the Germline and Causes Chromosome Abnormalities,” Proceedings of the National Academy of Sciences of the United States of America 107, no. 47 (November 23, 2010): 20405–10, http://www.pnas.org/content/107/47/20405.
60. “Our findings suggest that this colorant could cause harmful effects to humans if it is metabolized or absorbed through the skin.” F. M. Chequer, V. de Paula Venâncio, et al., “The Cosmetic Dye Quinoline Yellow Causes DNA Damage in Vitro,” Mutation Research/Genetic Toxicology and Environmental Mutagenesis 777 (January 1, 2015): 54–61, https://www.ncbi.nlm.nih.gov/pubmed/25726175.
61. Beer drinkers take note: “Beer is one source of NDMA, in which as much as 70 micrograms l(-1) has been reported in some types of German beer, although usual levels are much lower (10 or 5 micrograms l(-1)); this could mean a considerable intake for a heavy beer drinker of several liters per day.” The good news, the writer adds, is that in recent decades there’s been not only a reduction in the level of nitrates in food but also “greater control of exposure of malt to nitrogen oxides in beer making.” W. Lijinsky, “N-Nitroso Compounds in the Diet,” Mutation Research 443, nos. 1–2 (July 15, 1999): 129–38, https://www.ncbi.nlm.nih.gov/pubmed/10415436.
62. L. Robbiano, E. Mereto, C. Corbu, and G. Brambilla, “DNA Damage Induced by Seven N-nitroso Compounds in Primary Cultures of Human and Rat Kidney Cells,” Mutation Research 368, no. 1 (May 1996): 41–47, https://www.ncbi.nlm.nih.gov/pubmed/8637509.
63. The state of Massachusetts did a study in 1988 to get to grips with the prevalence of radon by county. It found that one in four houses apparently had levels over the EPA-identified level of 4pCi/L, which requires additional investigation. “Public Health Fact Sheet on Radon,” Health and Human Services, Commonwealth of Massachusetts, 2011, http://web.archive.org/web/20111121032816/http://www.mass.gov/eohhs/consumer/community-health/environmental-health/exposure-topics/radiation/radon/public-health-fact-sheet-on-radon.html.
64. “Most of the mercury that contaminates fish comes from household and industrial waste that is incinerated or released during the burning of coal and other fossil fuels. Products containing mercury that are improperly thrown in the garbage or washed down drains end up in landfills, incinerators, or sewage treatment facilities.” “Contaminants in Fish,” Washington State Department of Health, https://www.doh.wa.gov/CommunityandEnvironment/Food/Fish/ContaminantsinFish.
65. S. Horvath, “DNA Methylation Age of Human Tissues and Cell Types,” Genome Biology 14, no. 10 (2013): R115, https://www.ncbi.nlm.nih.gov/pubmed/24138928.
FIVE. A BETTER PILL TO SWALLOW
1. If Schrödinger couldn’t exactly answer the question of what life is, his book arguably did everything else but that. It’s credited with being a key influencer of the development of scientific thought in the twentieth century and helped lay the groundwork for the emergence of molecular biology and the discovery of DNA. E. Schrödinger, What Is Life? The Physical Aspect of the Living Cell (Cambridge, UK: Cambridge University Press, 1944).
2. V. L. Schramm and S. D. Schwartz, “Promoting Vibrations and the Function of Enzymes. Emerging Theoretical and Experimental Convergence,” Biochemistry 57, no. 24 (June 19, 2018): 3299–308, https://www.ncbi.nlm.nih.gov/pubmed/29608286.
3. “Cell Size and Scale,” Genetic Science Learning Center, University of Utah, http://learn.genetics.utah.edu/content/cells/scale/.
4. The macromolecular biological catalysts whose names end in -ase are enzymes.
5. Out of so many eminent quotes, this is one that scientists hold as wisdom for the ages: “The first principle is that you must not fool yourself—and you are the easiest person to fool.” R. P. Feynman, The Quotable Feynman, ed. Michelle Feynman (Princeton, NJ: Princeton University Press, 2015), 127.
6. After Sehgal’s employer was bought by the international health care company Wyeth, he resumed his work on rapamycin. “In 1999, the U.S. Food and Drug Administration approved rapamycin as a drug for transplant patients. Sehgal died a few years after the FDA approval, too soon to see his brainchild save the lives of thousands of transplant patients and go on to make Wyeth hundreds of millions of dollars.” B. Gifford, “Does a Real Anti-aging Pill Already Exist?,” Bloomberg, February 12, 2015, https://www.bloomberg.com/news/features/2015-02-12/does-a-real-anti-aging-pill-already-exist-.
7. The authors concluded that “up-regulation of a highly conserved response to starvation-induced stress is important for life span extension by decreased TOR signaling in yeast and higher eukaryotes.” R. W. Powers III, M. Kaeberlein, S. D. Caldwell, et al., “Extension of Chronological Life Span in Yeast by Decreased TOR Pathway Signaling,” Genes & Development 20, no. 2 (January 15, 2006): 174–84, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1356109/.
8. I. Bjedov, J. M. Toivonen, F. Kerr, et al., “Mechanisms of Life Span Extension by Rapamycin in the Fruit Fly Drosophilia melanogaster,” Cell Metabolism 11, no. 1 (January 6, 2010): 35–46, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2824086/.
9. The authors noted that these were the first results to show that mTOR could play a role in extending life: “Rapamycin may extend lifespan by postponing death from cancer, by retarding mechanisms of ageing, or both.” D. E. Harrison, R. Strong, Z. D. Sharp, et al., “Rapamycin Fed Late in Life Extends Lifespan in Genetically Heterogeneous Mice,” Nature 460 (July 8, 2009): 392–95, https://www.nature.com/articles/nature08221.
10. K. Xie, D. P. Ryan, B. L. Pearson, et al., “Epigenetic Alterations in Longevity Regulators, Reduced Life Span, and Exacerbated Aging-Related Pathology in Old Father Offspring Mice,” Proceedings of the National Academy of Sciences of the United States of America 115, no. 10 (March 6, 2018): E2348–57, https://www.pnas.org/content/115/10/E2348.
11. How do they pick so many winners? According to a press release, a Thomson Reuters’ executive explained it thus: “Highly-cited papers turn out to be one of the most reliable indicators of world-class research, and provide a glimpse at what research stands the best chance at being recognized with a Nobel Prize.” Thomson Reuters, “Web of Science Predicts 2016 Nobel Prize Winners,” PR Newswire, September 21, 2016, https://www.prnewswire.com/news-releases/web-of-science-predicts-2016-nobel-prize-winners-300331557.html.
12. In this case, the authors showed that 3 months of rapamycin increased middle-aged mice’s life expectancy by 60 percent as well as improving their healthspan. A. Bitto, K. I. Takashi, V. V. Pineda, et al., “Transient Rapamycin Treatment Can Increase Lifespan and Healthspan in Middle-Aged Mice,” eLife 5 (August 23, 2016): 5, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4996648/.
13. Low-level doses of a drug called everolimus were given to people over 65. Their response to flu vaccines improved by around 20 percent. A. Regalado, “Is This the Anti-aging Pill We’ve All Been Waiting For?,” MIT Technology Review, March 28, 2017, https://www.technologyreview.com/s/603997/is-this-the-anti-aging-pill-weve-all-been-waiting-for/.
14. Metformin, given to patients with diabetes, was particularly promising, two researchers noted. “While there are caveats with any study of this nature, the findings suggest that metformin may be affecting basic aging processes that underlie multiple chronic diseases and not just type II diabetes.” B. K. Kennedy, and J. K. Pennypacker, “Aging Interventions Get Human,” Oncotarget 6, no. 2 (January 2015): 590–91, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4359240/.
15. C. J. Bailey, “Metformin: Historical Overview,” Diabetologia 60 (2017): 1566–76, https://link.springer.com/content/pdf/10.1007%2Fs00125-017-4318-z.pdf.
16. Patients who took metformin displayed lower rates of mortality not only compared to diabetics but also compared to nondiabetics, the researchers found. Other results included less cancer and less cardiovascular disease in those being treated with metformin. J. M. Campbell, S. M. Bellman, M. D. Stephenson, and K. Lisy, “Metformin Reduces All-Cause Mortality and Diseases of Ageing Independent of Its Effect on Diabetes Control: A Systematic Review and Meta-analysis,” Ageing Research Reviews 40 (November 2017): 31–44, https://www.sciencedirect.com/science/article/pii/S1568163717301472.
17. R. A. DeFronzo, N. Barzilai, and D. C. Simonson, “Mechanism of Metformin Action in Obese and Lean Noninsulin-Dependent Diabetic Subjects,” Journal of Clinical Endocrinology & Metabolism 73, no. 6 (December 1991): 1294–301, https://www.ncbi.nlm.nih.gov/pubmed/1955512.
18. A. Martin-Montalvo, E. M. Mercken, S. J. Mitchell, et al., “Metformin Improves Healthspan and Lifespan in Mice,” Nature Communications 4 (2013): 2192, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3736576/.
19. V. N. Anisimov, “Metformin for Aging and Cancer Prevention,” Aging 2, no. 11 (November 2010): 760–74.
20. S. Andrzejewski, S.-P. Gravel, M. Pollak, and J. St-Pierre, “Metformin Directly Acts on Mitochondria to Alter Cellular Bioenergetics,” Cancer & Metabolism 2 (August 28, 2014): 12, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4147388/.
21. N. Barzilai, J. P. Crandall, S. P. Kritchevsky, and M. A. Espeland, “Metformin as a Tool to Target Aging,” Cell Metabolism 23 (June 14, 2016): 1060–65, https://www.cell.com/cell-metabolism/pdf/S1550-4131(16)30229-7.pdf.
22. C.-P. Wang, C. Lorenzo, S. L. Habib, et al. “Differential Effects of Metformin on Age Related Comorbidities in Older Men with Type 2 Diabetes,” Journal of Diabetes and Its Complications 31, no. 4 (2017): 679–86, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5654524/.
23. J. M. Campbell, S. M. Bellman, M. D. Stephenson, and K. Lisy, “Metformin Reduces All-Cause Mortality and Diseases of Ageing Independent of Its Effect on Diabetes Control: A Systematic Review and Meta-analysis,” Ageing Research Reviews 40 (November 2017): 31–44, https://www.ncbi.nlm.nih.gov/pubmed/28802803.
24. N. Howlader, A. M. Noone, M. Krapcho, et al., “SEER Cancer Statistics Review, 1975–2009,” National Cancer Institute, August 20, 2012, https://seer.cancer.gov/archive/csr/1975_2009_pops09/.
25. By the time you hit 90, the authors found, there’s a threefold decrease in the probability of developing cancer. If you make it to 100, from there the probability is minimal, 0 to 4 percent. N. Pavlidis, G. Stanta, and R. A. Audisio, “Cancer Prevalence and Mortality in Centenarians: A Systematic Review,” Critical Reviews in Oncology/Hematology 83, no. 1 (July 2012): 145–52, https://www.ncbi.nlm.nih.gov/pubmed/22024388.
26. I. Elbere, I. Silamikelis, M. Ustinova, et al., “Significantly Altered Peripheral Blood Cell DNA Methylation Profile as a Result of Immediate Effect of Metformin Use in Healthy Individuals,” Clinical Epigenetics 10, no. 1 (2018), https://doi.org/10.1186/s13148-018-0593-x.
27. B. K. Kennedy, M. Gotta, D. A. Sinclair, et al., “Redistribution of Silencing Proteins from Telomeres to the Nucleolus Is Associated with Extension of Lifespan in S. cerevisiae,” Cell 89, no. 3 (May 2, 1997): 381–91, https://www.ncbi.nlm.nih.gov/pubmed/?term=SIR4-42+sinclair+gotta; D. A. Sinclair and L. Guarente, “Extrachromosomal rDNA Circles—A Cause of Aging in Yeast,” Cell 91, no. 7 (December 26, 1997): 1033–42, https://www.ncbi.nlm.nih.gov/pubmed/9428525; D. Sinclair, K. Mills, and L. Guarente, “Accelerated Aging and Nucleolar Fragmentation in Yeast SGS1 Mutants,” Science 277, no. 5330 (August 29, 1997): 1313–16, https://www.ncbi.nlm.nih.gov/pubmed/9271578.
28. The research into resveratrol suggests that it is promising for both cancer and cardiovascular disease prevention. Resveratrol’s ability to act on tumor growth points to other possibilities. “Since tumor promoting agents alter the expression of genes whose products are associated with inflammation, chemoprevention of cardiovascular diseases and cancer may share the same common mechanisms.” E. Ignatowicz and W. Baer-Dubowska, “Resveratrol, a Natural Chemopreventive Agent Against Degenerative Diseases, “Polish Journal of Pharmacology 53, no. 6 (November 2001): 557–69, https://www.ncbi.nlm.nih.gov/pubmed/11985329.
29. The title of our paper is a combination of two Greek words: “xenos, the Greek word for stranger, and hormesis, the term for health benefits provided by mild biological stress, such as cellular damage or a lack of nutrition.” K. T. Howitz and D. A. Sinclair, “Xenohormesis: Sensing the Chemical Cues of Other Species,” Cell 133, no. 3 (May 2, 2008): 387–91, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2504011/.
30. An average glass of red wine contains about 1 to 3 mg of resveratrol. There is no resveratrol in white wine because resveratrol is produced largely by the skins of the grape, which are not used in white wine production. For more information on and dietary sources of resveratrol, see J. A. Baur and D. A. Sinclair, “Therapeutic Potential of Resveratrol: The in Vivo Evidence,” Nature Reviews Drug Discovery 5, no. 6 (June 2006): 493–506, https://www.ncbi.nlm.nih.gov/pubmed/16732220.
31. Continuing on from our work, the researchers proposed “a novel pathway by which products of the plant stress response confer stress tolerance and extend longevity in animals.” They also highlighted how xenohormesis may boost the health-giving and medicinal properties of plants, while also tackling issues around adapting in a world that’s forever changing. P. L. Hooper, P. L. Hooper, M. Tytell, and L. Vigh, “Xenohormesis: Health Benefits from an Eon of Plant Stress Response Evolution,” Cell Stress & Chaperones 15, no. 6 (November 2010): 761–70, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3024065/.
32. The implications for overweight humans were clear, we found. “This study shows that an orally available small molecule at doses achievable in humans can safely reduce many of the negative consequences of excess caloric intake, with an overall improvement in health and survival.” J. A. Baur, K. J. Pearson, N. L. Price, et al., “Resveratrol Improves Health and Survival of Mice on a High-Calorie Diet,” Nature 444, no. 7117 (November 1, 2006): https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4990206/.
33. J. A. Baur and D. A. Sinclair, “Therapeutic Potential of Resveratrol: The In Vivo Evidence,” Nature Reviews Drug Discovery 5, (2006): 493–506, https://www.nature.com/articles/nrd2060.
34. K. J. Pearson, J. A. Baur, K. N. Lewis, et al., “Resveratrol Delays Age-Related Deterioration and Mimics Transcriptional Aspects of Dietary Restriction Without Extending Life Span,” Cell Metabolism 8, no. 2 (August 6, 2008): 157–68, https://www.cell.com/cell-metabolism/abstract/S1550-4131%2808%2900182-4.
35. Our findings inevitably stirred up excitement in the media that drinking red wine may increase longevity, as well as admittedly a more sedate example, such as the article “Life-Extending Chemical Is Found in Some Red Wines” in the New York Times. K. T. Howitz, K. J. Bitterman, H. Y. Cohen, et al., “Small Molecule Activators of Sirtuins Extend Saccharomyces cerevisiae Lifespan,” Nature 425, no. 6954 (September 11, 2003): 191–96, https://www.ncbi.nlm.nih.gov/pubmed/12939617.
36. To combat aging in mice, we fed them the equivalent of about 100 glasses of red wine a day, not “1,000,” neither of which I recommend.
37. Martin-Montalvo et al., “Metformin Improves Healthspan and Lifespan in Mice.”
38. Forty patients with varying degrees of psoriasis took part in the study, of whom just over a third had “good to excellent” improvement, according to skin biopsies. J. G. Kreuger, M. Suárez-Fariñas, I. Cueto, et al., “A Randomized, Placebo-Controlled Study of SRT2104, a SIRT1 Activator, in Patients with Moderate to Severe Psoriasis,” PLOS One, November 10, 2015, https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0142081.
39. Hydrogen is used for hundreds of so-called redox reactions in the cell. NAD is a “hydrogen carrier.” The plus sign on “NAD+” indicates the form of NAD that doesn’t have a hydrogen atom attached. When it has a hydrogen atom attached, it is called “NADH.”
40. As NAD levels decline with age, so the body becomes more susceptible to disease, as two collaborators and I noted: “Restoration of NAD+ levels in old or diseased animals can promote health and extend lifespan, prompting a search for safe and efficacious NAD-boosting molecules that hold the promise of increasing the body’s resilience, not just to one disease, but to many, thereby extending healthy human lifespan.” L. Rajman, K. Chwalek, and D. A. Sinclair, “Therapeutic Potential of NAD-Boosting Molecules: The in Vivo Evidence,” Cell Metabolism 27, no. 3 (March 6, 2018): 529–47, https://www.ncbi.nlm.nih.gov/pubmed/29514064.
41. Y. A. R. White, D. C. Woods, Y. Takai, et al., “Oocyte Formation by Mitotically Active Germ Cells Purified from Ovaries of Reproductive Age Women,” Nature Medicine 18 (February 26, 2012): 413–21, https://www.nature.com/articles/nm.2669.
42. J. L. Tilly and D. A. Sinclair, “Germline Energetics, Aging, and Female Infertility,” Cell Metabolism 17, no. 6 (June 2013): 838–50, https://www.sciencedirect.com/science/article/pii/S1550413113001976.
43. Our paper in which we showed that SIRT2 is a key player in regulating lifespan in a living organism came out in 2014. B. J. North, M. A. Rosenberg, K. B. Jeganathan, et al., “SIRT2 Induces the Checkpoint Kinase BubR1 to Increase Lifespan,” EMBO Journal 33, no. 13 (July 1, 2014): 1438–53, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4194088/.
44. The researchers frame their results within the epidemic of obesity in developing countries and its link to reproductive health issues, including not only polycystic fibrosis but also gestational diabetes mellitus and endometrial cancer. They conclude that “Metformin may be a valuable alternative to, or adjunct for, modifying the toxic effects of obesity in these populations.” V. N. Sivalingam, J. Myers, S. Nicholas, et al., “Metformin in Reproductive Health, Pregnancy and Gynaecological Cancer: Established and Emerging Indications,” Human Reproduction 20, no. 6 (November 2014): 853–68, https://academic.oup.com/humupd/article/20/6/853/2952671.
45. “Chemotherapy-treated animals had significantly fewer offspring compared with all other treatment groups, whereas cotreatment with mTOR inhibitors preserved normal fertility.” K. N. Goldman, D. Chenette, R. Arju, et al., “mTORC1/2 Inhibition Preserves Ovarian Function and Fertility During Genotoxic Chemotherapy,” Proceedings of the National Academy of Sciences of the United States of America 114, no. 2 (March 21, 2017): 3196–91, http://www.pnas.org/content/114/12/3186.full.
46. Mice deficient in mTORC1, the authors found, “present spermatozoa with decreased motility, suggesting that mTORC1, besides controlling glandular size and seminal vesicle fluid composition, also regulates sperm physiology during passage through the epididymis.” P. F. Oliveira, C. Y. Cheng, and M. G. Alves, “Emerging Role for Mammalian Target of Rapamycin in Male Fertility,” Trends in Endocrinology and Metabolism 28, no. 3 (March 2017): 165–67, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5499664/.
47. The term “aging in place” refers to a recently evolved philosophy in Western countries of encouraging the elderly to grow old in places that meet their needs and circumstances. Australia, like so many other countries, is facing a demographic explosion in the number of its elderly, which has significant budgetary and societal implications. Australia’s 65- to 84-year-old population is expected to double or more by 2050. H. Bartlett and M. Carroll, “Aging in Place Down Under,” Global Ageing: Issues & Action 7, no. 2 (2011): 25–34, https://www.ifa-fiv.org/wp-content/uploads/global-ageing/7.2/7.2.bartlett.carroll.pdf.
SIX. BIG STEPS AHEAD
1. In a wide-ranging survey of interventions, the authors covered the health and life-prolonging benefits of various small molecules, exercising, and fasting regimes. “The current epidemics of obesity, diabetes, and related disorders constitute major impediments for healthy aging,” they wrote. “It is only by extending the healthy human lifespan that we will truly meet the premise of the Roman poet Cicero: ‘No one is so old as to think that he may not live a year.’ ” R. de Cabo, D. Carmona-Guttierez, M. Bernier, et al., “The Search for Antiaging Interventions: From Elixirs to Fasting Regimens,” Cell 157, no. 7 (June 19, 2014): 1515–26, https://www.cell.com/fulltext/S0092-8674(14)00679-5.
2. J. Yost and J. E. Gudjonsson, “The Role of TNF Inhibitors in Psoriasis Therapy: New Implications for Associated Comorbidities,” F1000 Medicine Reports 1, no. 30 (May 8, 2009), https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2924720/.
3. Killing off senescent cells in mice led to their having healthier lives, the author wrote in a story for Nature on Baker and van Deursen’s work. Their kidney function improved, and their hearts were more resilient to stress, they tended to explore their cages more, and developed cancers at a later age. E. Callaway, “Destroying Worn-out Cells Makes Mice Live Longer,” Nature, February 3, 2016, https://www.nature.com/news/destroying-worn-out-cells-makes-mice-live-longer-1.19287.
4. The impact of injected senescent cells on young mice was also remarkable in their destructiveness. “As early as two weeks after transplantation, the SEN mice showed impaired physical function as determined by maximum walking speed, muscle strength, physical endurance, daily activity, food intake, and body weight,” according to the NIH press release. “In addition, the researchers saw increased numbers of senescent cells, beyond what was injected, suggesting a propagation of the senescence effect into neighboring cells.” “Senolytic Drugs Reverse Damage Caused by Senescent Cells in Mice,” National Institutes of Health, July 9, 2018, https://www.nih.gov/news-events/news-releases/senolytic-drugs-reverse-damage-caused-senescent-cells-mice.
5. R.-M. Laberge, Y. Sun, A. V. Orjalo, et al., “MTOR Regulates the Pro-tumorigenic Senescence-Associated Secretory Phenotype by Promoting IL1A Translation,” Nature Cell Biology 17, no. 8 (July 6, 2015): 1049–61, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4691706/.
6. P. Oberdoerffer, S. Michan, M. McVay, et al., “DNA Damage–Induced Alterations in Chromatin Contribute to Genomic Integrity and Age-Related Changes in Gene Expression,” Cell 135, no. 5 (November 28, 2008): 907–18, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2853975/.
7. M. De Cecco, S. W. Criscione, E. J. Peckham, et al., “Genomes of Replicatively Senescent Cells Undergo Global Epigenetic Changes Leading to Gene Silencing and Activation of Transposable Elements,” Aging Cell 12, no. 2 (April 2013): 247–56, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3618682/.
8. “Adoptive transfer of T cells isolated from vaccine-treated tumor-bearing mice inhibited tumor growth in unvaccinated recipients, indicating that the iPSC vaccine promotes an antigen-specific anti-tumor T cell response,” the researchers found. N. G. Kooreman, K. Youngkyun, P. E. de Almeida, et al., “Autologous iPSC-Based Vaccines Elicit Anti-tumor Responses in Vivo,” Cell Stem Cell 22, no. 4 (April 5, 2018), http://www.cell.com/cell-stem-cell/fulltext/S1934-5909(18)30016-X.
9. Cells were taken from inside Streisand’s dog’s cheek and belly skin and sent to a lab in Texas. The cloning process resulted in four puppies, although one died shortly after birth. Streisand wrote that the dogs’ resembling her beloved Samantha physically was enough. “You can clone the look of a dog, but you can’t clone the soul. Still, every time I look at their faces, I think of my Samantha . . . and smile.” B. Streisand, “Barbara Streisand Explains: Why I Cloned My Dog,” New York Times, March 2, 2018, https://www.nytimes.com/2018/03/02/style/barbra-streisand-cloned-her-dog.html.
10. It is one of the most interesting and important papers I’ve ever read. C. E. Shannon, “A Mathematical Theory of Communication,” Bell System Technical Journal 27, no. 3 (July 1948): 379–423 and no. 4 (October 1948): 623–66, http://math.harvard.edu/~ctm/home/text/others/shannon/entropy/entropy.pdf.
11. The results of their experiments were extremely promising when it came to slowing down aging by putting a halt to the molecular changes that cause it. “Molecular alterations induced by in vivo reprogramming may potentially lead to a better maintenance of tissue homeostasis and lifespan extension,” they wrote. A. Ocampo, P. Reddy, P. Martinez-Redondo, et al., “In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming,” Cell 167, no. 7 (December 15, 2016): 1719–33, https://www.cell.com/cell/pdf/S0092-8674(16)31664-6.pdf.
12. “I feel a strong responsibility that it’s not just to make a first, but also make it an example,” he told the Associated Press. “Society will decide what to do next” as to whether such experiments should continue or be banned. M. Marchione, “Chinese Researcher Claims First Gene-Edited Babies,” Associated Press, November 26, 2018, https://www.apnews.com/4997bb7aa36c45449b488e19ac83e86d.
1. H. Singh, , A.N.D. Meyer, and E. J. Thomas, “The Frequency of Diagnostic Errors in Outpatient Care: Estimations from Three Large Observational Studies Involving US Adult Populations,” BMJ Quality & Safety 23, no. 9 (August 12, 2014), https://qualitysafety.bmj.com/content/23/9/727.
2. M. Jain, S. Koren, K. H. Miga, et al., “Nanopore Sequencing and Assembly of a Human Genome with Ultra-long Reads,” Nature Biotechnology 36, no. 4 (2018): 338–45, https://www.nature.com/articles/nbt.4060.
3. The evolution of such technology is tied by its inventors to benefiting the community, rather than corporations. That said, this particular company was also promoting the idea of a “coin,” or digital currency, not for investment or as a security, according to the writer, but to incentivize individuals to share their genomic data with scientists. “The underlying idea is to incentivize users to make their personal genomic data available for biomedical and health-related research for the greater good of medical discovery.” B. V. Bigelow, “Luna DNA Uses Blockchain to Share Genomic Data as a ‘Public Benefit,’ ” Exome, January 22, 2018, https://xconomy.com/san-diego/2018/01/22/luna-dna-uses-blockchain-to-share-genomic-data-as-a-public-benefit/.
4. S. W. H. Lee, N. Chaiyakunapruk, and N. M. Lai, “What G6PD-Deficient Individuals Should Really Avoid,” British Journal of Clinical Pharmacology 83, no. 1 (January 2017): 211–12, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5338146/; “Glucose-6-Phosphate Dehydrogenase Deficiency,” MedlinePlus, https://medlineplus.gov/ency/article/000528.htm.
5. J. A. Sparano, R. J. Gray, D. F. Makower, et al., “Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer,” New England Journal of Medicine 379 (July 12, 2018): 111–21, https://www.nejm.org/doi/full/10.1056/NEJMoa1804710.
6. K. A. Liu and N. A. D. Mager, “Women’s Involvement in Clinical Trials: Historical Perspective and Future Implications,” Pharmacy Practice 14, no. 1 (January–March 2016): 708–17, https://www.pharmacypractice.org/journal/index.php/pp/article/view/708/424.
7. Female mice that had received mTOR treatment lived 20 percent longer than the untreated mice in the control group. Leibniz Institute on Aging, Fritz Lipmann Institute, “Less Is More? Gene Switch for Healthy Aging Found,” Medical Xpress, May 25, 2018, https://medicalxpress.com/news/2018-05-gene-healthy-aging.html.
8. Swedish records showed that in every single year since 1800, women had lived longer than men. “This remarkably consistent survival advantage of women compared with men in early life, in late life, and in total life is not confined to Sweden but is seen in every country in every year for which reliable birth and death records exist. There may be no more robust pattern in human biology,” the authors noted. S. N. Austad and A. Bartke, “Sex Differences in Longevity and in Responses to Anti-aging Interventions: A Mini-review,” Gerontology 62, no. 2 (2015): 40–46, https://www.karger.com/Article/FullText/381472.
9. E. J. Davis, I. Lobach, and D. B. Dubal, “Female XX Sex Chromosomes Increase Survival and Extend Lifespan in Aging Mice,” Aging Cell 18, no. 1 (February 2019), e12871, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351820/.
10. One example where pharmacogenomics information is already used to inform drug prescription is in the treatment of HIV. Patients with HIV are tested for a specific genetic variant to see if they may have a bad reaction to an antiviral drug called abacavir, according to a fact sheet on the National Human Genome Research Institute’s website; see “Frequently Asked Questions About Pharmacogenomics,” National Human Genome Research Institute, May 2, 2016, https://www.genome.gov/27530645/.
11. The autopsy of a mummified corpse of a fourteenth-century Italian warlord lent credence to centuries-old rumors that days after his triumphant conquest of Treviso, 38-year-old Cangrande I della Scala had been poisoned with digitalis. H. Thompson, “Poison Hath Been This Italian Mummy’s Untimely End,” Smithsonian.com, January 14, 2015, https://www.smithsonianmag.com/science-nature/poison-hath-been-italian-mummys-untimely-end-digitalis-foxglove-180953822/.
12. M. Vamos, J. W. Erath, and S. H. Hohnloser, “Digoxin-Associated Mortality: A Systematic Review and Meta-analysis of the Literature,” European Heart Journal 36, no. 28 (July 21, 2015): 1831–38, https://academic.oup.com/eurheartj/article/36/28/1831/2398087.
13. M. N. Miemeijer, M. E. van den Berg, J. W. Deckers, et al., “ABCB1 Gene Variants, Digoxin and Risk of Sudden Cardiac Death in a General Population,” BMJ Heart 101, no. 24 (December 2015), https://heart.bmj.com/content/101/24/1973?heartjnl-2014-307419v1=; A. Oni-Orisan and D. Lanfear, “Pharmacogenomics in Heart Failure: Where Are We Now and How Can We Reach Clinical Application?,” Cardiology in Review 22, no. 5 (September 1, 2015): 193–98, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4329642/.
14. Back in 2015, Johnson felt it would be only another ten years until our genome is defined and stored for use while we’re alive. “When that happens, using genetic information to inform decisions about the right drug and the right dose will likely involve computerized approaches that marry the genetic data with knowledge about drugs and genes, to lead to a personalized treatment recommendation,” she wrote. J. A. Johnson, “How Your Genes Influence What Medicines Are Right for You,” Conversation, November 20, 2015, https://theconversation.com/how-your-genes-influence-what-medicines-are-right-for-you-46904.
15. That seems to be changing, though, according to the authors, as more of their colleagues publish papers on this area, ensuring “that the gut microbiota are moving out of the shadows and are moving towards centre stage in drug safety studies and personalized health care.” I. D. Wilson and J. K. Nicholson, “Gut Microbiome Interactions with Drug Metabolism, Efficacy and Toxicity,” Translational Research: The Journal of Laboratory and Clinical Medicine 179 (January 2017): 204–22, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5718288/; see also B. Das, T. S. Ghosh, S. Kedia, et al., “Analysis of the Gut Microbiome of Rural and Urban Healthy Indians Living in Sea Level and High-Altitude Areas,” Nature Scientific Reports 8 (July 4, 2018), https://www.nature.com/articles/s41598-018-28550-3.
16. P. Lehouritis, J. Cummins, M. Stanton, et al., “Local Bacteria Affect the Efficacy of Chemotherapeutic Drugs,” Nature Scientific Reports 5 (September 29, 2015), https://www.nature.com/articles/srep14554.
17. The wait increased from 18.5 days in 2014 to 24 days in 2017, according to a study by MerrittHawkins. B. Japsen, “Doctor Wait Times Soar 30% in Major U.S. Cities,” Forbes, March 19, 2017, https://www.forbes.com/sites/brucejapsen/2017/03/19/doctor-wait-times-soar-amid-trumpcare-debate/#7ac0753b2e74.
18. The website of myDNAge offers some encouragement: “You can’t change your genes, but you can change how your genes behave through epigenetics,” runs the tagline. All you have to do is send in your bodily fluids (blood or urine) and they’ll determine your biological age by measuring the epigenetic modifications on your DNA. “Reveal Your Biological Age Through Epigenetics,” myDNAge, 2017, https://www.mydnage.com/. TeloYears offers to track your cellular age based on your telomeres, which, it informs its website readers, are “the caps on your DNA that, unlike your ancestry, you can actually change.” TeloYears, 2018, https://www.teloyears.com/home/.
19. M. W. Snyder, M. Kircher, A. J. Hill, et al., “Cell-free DNA Comprises an in Vivo Nucleosome Footprint That Informs Its Tissues-of-Origin,” Cell 164, nos. 1–2 (January 14, 2016): 57–68, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4715266/.
20. “Global Automotive Level Sensor Market Analysis, Trends, Drivers, Challenges & Forecasts 2018–2022, with the Market Set to Grow at a CAGR of 4.13%—ResearchAndMarkets.com,” Business Wire, May 2, 2018, https://www.businesswire.com/news/home/20180502005988/en/Global-Automotive-Level-Sensor-Market-Analysis-Trends.
21. University of Cincinnati senior scientist Jason Heikenfeld and his team worked with a US Air Force Research Laboratory in Ohio on a simple way to keep track of how airmen respond to everything from diet, stress, and injury to medication and disease. They came up with patches that both stimulate and monitor sweat and then send data to a smartphone. J. Heikenfeld, “Sweat Sensors Will Change How Wearables Track Your Health,” IEEE Spectrum, October 22, 2014, https://spectrum.ieee.org/biomedical/diagnostics/sweat-sensors-will-change-how-wearables-track-your-health.
22. Owlstone has already started lung cancer clinical trials in the United Kingdom, testing hundreds of patients for early signs. In the United Kingdom, it notes on its website, “only 14.5 percent of people are diagnosed with early stage, treatable lung cancer. If we are able to increase this to 25% we’d save 10,000 lives in the U.K. alone.” D. Sfera, “Breath Test Detects Cancer Markers,” Medium, August 2, 2018, https://medium.com/@TheRealDanSfera/breath-test-detects-cancer-markers-c57dcc86a583. With advancements in drug treatments, early detection, the company points out, is a more powerful tool to save lives than the development of new drugs. “A Breathalyzer for Disease,” Owlstone Medical, https://www.owlstonemedical.com/.
23. Two examples are Öura Ring (https://ouraring.com/) and Motiv Ring (https://mymotiv.com/).
24. “A growing body of evidence suggests that an array of mental and physical conditions can make you slur your words, elongate sounds, or speak in a more nasal tone.” R. Robbins, “The Sound of Your Voice May Diagnose Disease,” Scientific American, June 30, 2016, https://www.scientificamerican.com/article/the-sound-of-your-voice-may-diagnose-disease/.
25. Researchers used the amount of time subjects took to press and release a key on the computer and converted it to a Parkinson’s disease motor index. L. Giancardo, A. Sánchez-Ferro, T. Arroyo-Gallego, et al., “Computer Keyboard Interaction as an Indicator of Early Parkinson’s Disease,” Nature Scientific Reports 6 (October 5, 2016): 34468, https://www.nature.com/articles/srep34468.
26. For a more detailed account of what’s just around the corner, this book is well worth the read: E. Topol, The Creative Destruction of Medicine: How the Digital Revolution Will Create Better Health Care, Kindle edition (New York: Basic Books, 2011).
27. I am an investor in and former member of the board of InsideTracker, a Segterra company based in Massachusetts, http://www.insidetracker.com/. I have invested in and advise the company, and I am an inventor on a patent application filed to calculate biological age based on markers that are known to change with age.
28. The app is called Clue. E. Avey, “ ‘The Clue App Saved My Life’: Early Detection Through Cycle Tracking,” Clued In, September 24, 2017, https://medium.com/clued-in/the-clue-app-saved-my-life-early-detection-through-cycle-tracking-91732dd29d25.
29. Over the past three decades, a new infectious disease has appeared every single year in some part of the world. In total, researchers put the number of unknown viruses in birds and mammals that could infect humans between 631,000 and 827,000. Though there are ongoing efforts to identify all these viruses, “we likely won’t ever be able to predict which will spill over next; even long-known viruses like Zika, which was discovered in 1947, can suddenly develop into unforeseen epidemics.” E. Yong, “The Next Plague Is Coming. Is America Ready?,” The Atlantic, July–August 2018, https://www.theatlantic.com/magazine/archive/2018/07/when-the-next-plague-hits/561734/.
30. L. M. Mobula, M. MacDermott, C. Hoggart, et al., “Clinical Manifestations and Modes of Death Among Patients with Ebola Virus Disease, Monrovia, Liberia, 2014,” American Journal of Tropical Medicine and Hygiene 98, no. 4 (April 2018): 1186–93, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5928808/.
31. The measures to prepare for a future pandemic that Gates argues in an editorial should be put into play include building up public health systems in countries vulnerable to epidemics and mimicking how the military preps for war with “germ games and other preparedness exercises so we can better understand how diseases will spread, how people will respond in a panic, and how to deal with things like overloaded highways and communications systems.” B. Gates, “Bill Gates: A New Kind of Terrorism Could Wipe Out 30 Million People in Less than a Year—and We Are Not Prepared,” Business Insider, February 18, 2017, http://www.businessinsider.com/bill-gates-op-ed-bio-terrorism-epidemic-world-threat-2017-2.
32. It was only after a 2009 law was passed that companies had to inform the public and the government of any breaches. Since then, the volume of breaches at health care providers has consistently climbed, from 150 in 2010 to 250 seven years later. Consumer Reports, “Hackers Want Your Medical Records. Here’s How to Keep Your Info from Them,” Washington Post, December 17, 2018, https://www.washingtonpost.com/national/health-science/hackers-want-your-medical-records-heres-how-to-keep-your-info-from-them/2018/12/14/4a9c9ab4-fc9c-11e8-ad40-cdfd0e0dd65a_story.html?utm_term=.ea4e14662e4a.
33. A. Sulleyman, “NHS Cyber Attack: Why Stolen Medical Information Is So Much More Valuable than Financial Data,” Independent, May 12, 2017, https://www.independent.co.uk/life-style/gadgets-and-tech/news/nhs-cyber-attack-medical-data-records-stolen-why-so-valuable-to-sell-financial-a7733171.html.
34. S. S. Dominy, C. Lynch, F. Ermini, et al., “Porphyromonas gingivalis in Alzheimer’s Disease Brains: Evidence for Disease Causation and Treatment with Small-Molecule Inhibitors,” Science Advances 5, no. 1 (January 23, 2019), http://advances.sciencemag.org/content/advances/5/1/eaau3333.full.pdf.
35. That rate of decline continued over the next few years, thanks to fewer older adults requiring hospitalization for pneumonia. “By 2009, more than half the nationwide decline in pneumonia hospitalizations could be attributed to older adults, with some 70,000 fewer annual hospitalizations for those age 85 and older.” “Infant Vaccine for Pneumonia Helps Protect Elderly,” VUMC Reporter, July 11, 2013, http://news.vumc.org/2013/07/11/infant-vaccine-for-pneumonia-helps-protect-elderly/.
36. M. R. Moore, R. Link-Gelles, W. Schaffner, et al., “Impact of 13-Valent Pneumococcal Conjugate Vaccine Used in Children on Invasive Pneumococcal Disease in Children and Adults in the United States: Analysis of Multisite, Population-Based Surveillance,” Lancet Infectious Diseases 15, no. 3 (March 2015): 301–09, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4876855/.
37. If you have a companion animal, it can still get the Lyme disease vaccine.
38. “ ‘The [research and development] model is broken,’ said Kate Elder, vaccines policy adviser at Médecins sans Frontières. ‘Priorities are chosen based on where the money is . . . diseases predominantly in the developed world,’ she said.” H. Collis, “Vaccines Need a New Business Model,” Politico, April 27, 2016, https://www.politico.eu/article/special-report-vaccines-need-a-new-business-model/.
39. “The analysis was conducted by Ronald Evens, adjunct research professor at Tufts CSDD and Tufts University School of Medicine and adjunct professor in the Thomas J. Long School of Pharmacy and Health Sciences at University of the Pacific, using data from company reports, periodic biotechnology reports from the Pharmaceutical Research and Manufacturers of America, IMS sales data, and FDA and Tufts CSDD databases.” M. Powers, “Tufts: The Vaccine Pipeline Is Soaring and Global Sales Could Hit $40B by 2020,” BioWorld, April 21, 2016, http://www.bioworld.com/content/tufts-vaccine-pipeline-soaring-and-global-sales-could-hit-40b-2020.
40. Africa has borne the brunt of more than 90 percent of the globe’s malaria cases and deaths. “Malaria,” World Health Organization, November 19, 2018, https://www.who.int/news-room/fact-sheets/detail/malaria.
41. “Ghana, Kenya and Malawi to Take Part in WHO Malaria Vaccine Pilot Programme,” World Health Organization, Regional Office for Africa, April 24, 2017, http://www.afro.who.int/news/ghana-kenya-and-malawi-take-part-who-malaria-vaccine-pilot-programme.
42. Crises such as an Ebola outbreak highlight a fundamental flaw in medical research and drug development, researchers told a Boston Globe reporter. Unless there’s public concern, researchers and pharmaceutical companies have “scant incentive to quickly develop vaccines and drugs for little-seen diseases.” Y. Abutaleb, “Speeding Up the Fight Against Ebola, Other Diseases,” Boston Globe, August 22, 2014, https://www.bostonglobe.com/metro/2014/08/21/faster-development-vaccines-and-drugs-targeting-diseases-such-ebola-horizon/yrkrN56VgehrSzCtETPzzH/story.html.
43. An equally sobering statistic is that each day twenty people die waiting for a transplant, while just one organ donor can save eight lives. “Transplant Trends,” United Network for Organ Sharing, https://unos.org/data/.
44. That said, Crouch notes, in Cruise’s most recent Mission Impossible epic, “Mission: Impossible—Fallout,” the 56-year-old Cruise’s character, Ethan Hunt, appears to acknowledge that with advancing years come limitations, as in, for example, needing a younger associate to help him defeat a bad guy in a lengthy brawl or having an eye for ever-younger girlfriends. I. Crouch, “The Wilford Brimley Meme That Helps Measure Tom Cruise’s Agelessness,” “Rabbit Holes,” New Yorker, August 11, 2018, https://www.newyorker.com/culture/rabbit-holes/the-wilford-brimley-meme-that-helps-measure-tom-cruises-agelessness.
EIGHT. THE SHAPE OF THINGS TO COME
1. A. Jenkins, “Which 19th century physicist famously said that all that remained to be done in physics was compute effects to another decimal place?,” Quora, June 26, 2016, https://www.quora.com/Which-19th-century-physicist-famously-said-that-all-that-remained-to-be-done-in-physics-was-compute-effects-to-another-decimal-place.
2. “The Road Ahead (Bill Gates book),” Wikipedia, https://en.wikipedia.org/wiki/The_Road_Ahead_(Bill_Gates_book)#cite_note-Weiss06-3.
3. Kelly added a key point to that excellent mantra: “It’s by use [that] we figure out what things are good for. Which is perhaps another way of saying “Go with the flow and see where it takes you.” J. Altucher, “One Rule for Predicting What You Never Saw Coming . . . ,” The Mission, July 15, 2016, https://medium.com/the-mission/kevin-kelly-one-rule-for-predicting-what-you-never-saw-coming-1e9e4eeae1da.
4. L. Gratton and A. Scott, The 100 Year Life: Living and Working in an Age of Longevity (London and New York: Bloomsbury Publishing, 2018).
5. A phrase originating with the theologian Theodore Parker but made famous by Dr. Martin Luther King, Jr., and used several times by President Barack Obama.
6. It was a time of sufficient population density that people began to take an interest in their appearance, notably changing how they looked with beads and pigments. E. Trinkaus, “Late Pleistocene Adult Mortality Patterns and Modern Human Establishment,” Proceedings of the National Academy of Sciences of the United States of America 108, no. 4 (January 25, 2011): 12267–71, https://www.ncbi.nlm.nih.gov/pubmed/21220336.
7. Up until 4,000 years ago, human numbers were minimal, according to a writer at the Global Environmental Alert Service. Since then, growth has climbed ever faster, the rate peaking in the 1960s. In 2012, the United Nations estimated that by the end of the century world population will be 10.1 billion. “One Planet, How Many People? A Review of Earth’s Carrying Capacity,” UNEP Global Environmental Alert Service, June 2012, https://na.unep.net/geas/archive/pdfs/geas_jun_12_carrying_capacity.pdf.
8. Similar sentiments are held by the American public, according to a Pew Research Center survey, which found that 59 percent took a “pessimistic view about the effect of population growth saying it will be a major problem because there will not be enough food and resources to go around.” “Attitudes and Beliefs on Science and Technology Topics,” Pew Research Center, Science & Society, January 29, 2015, http://www.pewinternet.org/2015/01/29/chapter-3-attitudes-and-beliefs-on-science-and-technology-topics/#population-growth-and-natural-resources-23-point-gap.
9. M. Blythe, “Professor Frank Fenner, Microbiologist and Virologist,” Australian Academy of Science, 1992 and 1993, https://www.science.org.au/learning/general-audience/history/interviews-australian-scientists/professor-frank-fenner.
10. Fenner contrasted the fate of humanity with that of the residents of Easter Island, who were decimated in the 1600s by their reliance on the forests they themselves had cut down. Dwindling food sources, followed by civil war and the arrival of foreign sailors who brought violence and disease, made its population plunge to 111 individuals by 1872. Though the numbers have since rebounded, Fenner’s views on humanity’s future did not hold up such a generous possibility, he told a reporter from the Australian. “As the population keeps growing to seven, eight or nine billion, there will be a lot more wars over food,” he said. “The grandchildren of today’s generations will face a much more difficult world.” C. Jones, “Frank Fenner Sees No Hope for Humans,” Australian, June 16, 2010, https://www.theaustralian.com.au/higher-education/frank-fenner-sees-no-hope-for-humans/news-story/8d77f0806a8a3591d47013f7d75699b9?nk=099645834c69c221f8ecf836d72b8e4b-1520269044.
11. “There are 925 million people who go hungry every day, despite the amazing economic prosperity we’ve enjoyed over the past 60 years,” wrote Michael Schuman in a piece on Malthus’s predictions for Time. “And twice in the past three years we’ve suffered through destabilizing spikes in the cost of food that have trapped tens of millions in poverty. Today, prices are nearly at historic highs.” M. Schuman, “Was Malthus Right?,” Time, July 15, 2011, http://business.time.com/2011/07/15/was-malthus-right/.
12. P. R. Ehrlich, The Population Bomb (New York: Ballantine Books, 1968), 1.
13. Ibid., 3.
14. Some of the statistics are simply mind-boggling. Not only is our global population growing by 74 million a year, but “we have consumed more resources in the last 50 years than the whole of humanity before us.” S. Dovers, “Population and Environment: A Global Challenge,” Australian Academy of Science, August 7, 2015, https://www.science.org.au/curious/earth-environment/population-environment.
15. “Municipal Solid Waste,” Environmental Protection Agency, March 29, 2016, https://archive.epa.gov/epawaste/nonhaz/municipal/web/html/.
16. If you run your dryer two hundred times a year, according to a Guardian column on the carbon footprint of everyday items, that would generate approximately half a ton of CO2. M. Berners-Lee and D. Clark, “What’s the Carbon Footprint of . . . a Load of Laundry?,” Guardian, November 25, 2010, https://www.theguardian.com/environment/green-living-blog/2010/nov/25/carbon-footprint-load-laundry.
17. MIT students estimated that “Whether you live in a cardboard box or a luxurious mansion, whether you subsist on homegrown vegetables or wolf down imported steaks, whether you’re a jet-setter or a sedentary retiree, anyone who lives in the U.S. contributes more than twice as much greenhouse gas to the atmosphere as the global average.” Massachusetts Institute of Technology, “Carbon Footprint of Best Conserving Americans Is Still Double Global Average,” Science Daily, https://www.sciencedaily.com/releases/2008/04/080428120658.htm.
18. Residents of Luxembourg, Qatar, Australia, and Canada have greater average levels of consumption and waste, according to the Global Footprint Network, https://www.footprintnetwork.org/.
19. “Country Overshoot Days,” Earth Overshoot Day, https://www.overshootday.org/about-earth-overshoot-day/country-overshoot-days/.
20. The Yale economist William D. Nordhaus has argued that although 2° Celsius is not obtainable, 2.5° might be possible, although it would take extreme global policy measures to get there. W. D. Nordhaus, “Protections and Uncertainties about Climate Change in an Era of Minimal Climate Policies,” Cowles Foundation for Research in Economics, Yale University, December 2016, https://cowles.yale.edu/sites/default/files/files/pub/d20/d2057.pdf.
21. Pennsylvania State University professor David Titley conjures up a powerful metaphor for gradations in temperature limits over 2°C. Think of 2° as the 30-mph signposted speed for a truck going down a hill. Then each fraction or whole degree beyond 2 increases the speed of the descending truck and consequently the ever-shortening odds of disaster. D. Titley, “Why Is Climate Change’s 2 Degrees Celsius of Warming Limit So Important?,” The Conversation, August 23, 2017, https://theconversation.com/why-is-climate-changes-2-degrees-celsius-of-warming-limit-so-important-82058.
22. The Great Barrier Reef isn’t only one of the most stunning and unique ecosystems in the world, it’s also a huge part of Australia’s tourism industry. It rakes in $4.5 billion annually in revenue from tourists and provides jobs for 70,000 people. B. Kahn, “Bleaching Hits 93 Percent of the Great Barrier Reef,” Scientific American, April 20, 2016, https://www.scientificamerican.com/article/bleaching-hits-93-percent-of-the-great-barrier-reef/.
23. Unless the global temperature increase can be held down to 1.5°C, the reef, whose area is equivalent to the size of Italy, will not survive, coral scientists have concluded. N. Hasham, “Australian Governments Concede Great Barrier Reef Headed for ‘Collapse,’ ” Sydney Morning Herald, July 20, 2018, https://www.smh.com.au/politics/federal/australian-governments-concede-great-barrier-reef-headed-for-collapse-20180720-p4zsof.html.
24. By the end of the century, scientists predict, the sea level could rise by between .5 and 1.4 meters. A rise of 5 meters could swamp 3.2 million square kilometers of coastlines, impacting 670 million people. As warming waters impact Greenland and Antarctic ice, they will speed up the pace of the sea level’s rising worldwide. “Study Says 1 Billion Threatened by Sea Level Rise,” Worldwatch Institute, January 27, 2019, http://www.worldwatch.org/node/5056.
25. The WHO breaks down its estimate of 250,000 extra deaths due to climate change per year between 2030 and 2050 into these categories: heat exposure killing the elderly (38,000), diarrhea (48,000), malaria (60,000), and childhood undernutrition (95,000). “Climate Change and Health,” World Health Organization, February 1, 2018, http://www.who.int/mediacentre/factsheets/fs266/en/.
26. Max Planck’s Wissenschaftliche Selbstbiographie was translated from German by Frank Gaynor and published as A Scientific Autobiography in 1949 by Greenwood Press Publishers, Westport, Connecticut.
27. Brexit is a good example of this, Onder noted. Whereas only a quarter of youths voted to leave the European Union, six out of ten people 65 or older voted to leave. H. Onder, “The Age Factor and Rising Nationalism,” Brookings, July 18, 2016, https://www.brookings.edu/blog/future-development/2016/07/18/the-age-factor-and-rising-nationalism/.
28. Those who are 80 or older—the “oldest-old,” according to the United Nations—are increasing in number faster than are older people (those over 60) overall. In 2015, there were 125 million 80-plus-year-olds; by 2050 there are expected to be close to 450 million. Department of Economic and Social Affairs, Population Division, World Population Ageing 2015 (New York: United Nations, 2015), http://www.un.org/en/development/desa/population/publications/pdf/ageing/WPA2015_Report.pdf.
29. “Strom Thurmond’s Voting Records,” Vote Smart, https://votesmart.org/candidate/key-votes/53344/strom-thurmond.
30. In an incisive piece in the Nation, UCLA and Columbia Law ’School professor Kimberlé Williams Crenshaw highlighted some of the abhorrent double standards surrounding Thurmond. “For most critics of sexual racism, this is simply a textbook case of a white man getting away with sexual behavior that would have sent an African-American man to his death,” she wrote. Indeed, in 1942, then Judge Thurmond sent a black man to the electric chair “based on an alleged rape victim’s cross-race identification, testimony now known to be extremely unreliable.” K. W. Crenshaw, “Was Strom a Rapist?,” Nation, February 26, 2004, https://www.thenation.com/article/was-strom-rapist/.
31. The elderly poor’s only alternatives were family, friends, or the poorhouse. B. Veghte, “Social Security, Past, Present and Future,” National Academy of Social Insurance, August 13, 2015, https://www.nasi.org/discuss/2015/08/social-security%E2%80%99s-past-present-future.
32. Men who reached age 65 in 1940 lived on average for another 12.7 years. By 1990, that average had climbed to 15.3 years. Women’s average life expectancy for the same period (assuming they, too, survived to 65), increased by almost 5 years, to 19.6 years. “Life Expectancy for Social Security,” Social Security, https://www.ssa.gov/history/lifeexpect.html.
33. By 2015, around 8 percent of the elderly were below the poverty line. “Per Capita Social Security Expenditures and the Elderly Poverty Rate, 1959–2015,” The State of Working America, September 26, 2014, http://www.stateofworkingamerica.org/chart/swa-poverty-figure-7r-capita-social-security/.
34. “Actuarial Life Table,” Social Security, 2015, https://www.ssa.gov/oact/STATS/table4c6.html.
35. William Safire tracked down the source of this quote for the New York Times in 2007: it was Kirk O’Donnell, a top aide to Tip O’Neill. W. Safire, “Third Rail,” New York Times, February 18, 2007, http://www.nytimes.com/2007/02/18/magazine/18wwlnsafire.t.html.
36. “Social Security Beneficiary Statistics,” Social Security, https://www.ssa.gov/oact/STATS/OASDIbenies.html.
37. “Quick Facts: United States,” United States Census Bureau, https://www.census.gov/quickfacts/fact/table/US/PST045217.
38. Older voters have notably more impact when it comes to the primaries, according to Harvard professor of government Stephen Ansolabehere. “Older people tend to vote more often in primaries,” he says. “And since the primary turnout tends to be lower, that means that bloc can be even more important.” D. Bunis, “The Immense Power of the Older Voter,” AARP Bulletin, April 30, 2018, https://www.aarp.org/politics-society/government-elections/info-2018/power-role-older-voters.
39. The days of long summer vacations (leaving continental Europe’s capitals all but empty), early retirement, and blanket medical insurance seem to be becoming a thing of the past in Europe, wrote the Washington Post’s Edward Cody. “In the new reality, workers have been forced to accept salary freezes, decreased hours, postponed retirements and health-care reductions.” E. Cody, “Europeans Shift Long-Held View That Social Benefits Are Untouchable,” Washington Post, April 24, 2011, https://www.washingtonpost.com/world/europeans-shift-long-held-view-that-social-benefits-are-untouchable/2011/02/09/AFLdYzdE_story.html?utm_term=.bcf29d628eea.
40. Part of the reason there’s such a stark difference in life expectancy, according to public health researchers, is the disappearance of smoking from the lifestyles of the rich and educated. S. Tavernise, “Disparity in Life Spans of the Rich and the Poor Is Growing,” New York Times, February 12, 2016, https://www.nytimes.com/2016/02/13/health/disparity-in-life-spans-of-the-rich-and-the-poor-is-growing.html.
41. Joint Committee on Taxation, U.S. Congress, “History, Present Law, and Analysis of the Federal Wealth Transfer Tax System,” JCX-52-15, March 16, 2015, https://www.jct.gov/publications.html?func=startdown&id=4744.
42. “SOI Tax Stats—Historical Table 17,” IRS, August 21, 2018, https://www.irs.gov/statistics/soi-tax-stats-historical-table-17.
43. Horses pulling carriages littered the streets with dung. Corpses rotted in overflowing graveyards. Garbage piled up in the streets. L. Jackson, Dirty Old London: The Victorian Fight Against Filth (New Haven, CT: Yale University Press, 2015).
44. W. Luckin, “The Final Catastrophe—Cholera in London, 1886,” Medical History 21, no. 1 (January 1977): 32–42, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1081893/?page=5.
45. H. G. Wells highlighted the possibility of world destruction stemming from the splitting of the atom, wrote Smithsonian writer Brian Handwerk, as well as the future threat of portable devices capable of mass destruction. “Wells also clearly saw the dangers of nuclear proliferation, and the doomsday scenarios that might arise both when nations were capable of ‘mutually assured destruction’ and when non-state actors or terrorists got into the fray.” B. Handwerk, “The Many Futuristic Predictions of H. G. Wells That Came True,” Smithsonian.com, September 21, 2016, https://www.smithsonianmag.com/arts-culture/many-futuristic-predictions-hg-wells-came-true-180960546/.
46. According to the author and film historian Mark Clark, Wells’s sci-fi classic Things to Come and the subsequent 1936 film, which Clark claims was made under the author’s creative control, was his attempt “to save the world. Literally.” It’s a story of a world racked by war, only to be offered salvation by the Airmen. “They are a society of scientists and engineers who, hidden away from the rest of the world, have made great scientific advances and are now prepared to lead humanity to a brighter future—so long as it submits to their benevolent rule.” M. Clark, “Common Thread: Wells and Roddenberry,” Onstage and Backstage, July 29, 2013, https://onstageandbackstage.wordpress.com/tag/gene-roddenberry/.
47. Roddenberry’s work echoed Wells’s utopian-themed writing, Clark has pointed out. Ibid.
48. As Wells noted time and again in his writings, these are the only two options for humanity.
49. A. van Leeuwenhoek, “Letters 43–69,” Digitale Bibliotheek oor de Nederlandse, April 25, 1679, http://www.dbnl.org/tekst/leeu027alle03_01/leeu027alle03_01_0002.php#b0043.
50. We have long been losing the battle to balance technological developments in goods and services with the environmental impact of population growth. “One Planet, How Many People?”’
51. Edward O. Wilson, The Future of Life (2002; repr., New York: Vintage Books), 33. In a review in the New Yorker (March 4, 2002): “Wilson, an eminent evolutionary biologist, shows the extent to which human prosperity, even in the information age, rests on the foundation of a diverse natural world, since the more species any ecosystem has, the more stable and productive it will be.”
52. Nowhere has the debate about a land’s carrying capacity been greater than in Australia. The Dutch may have been the first Europeans to discover the great southern land Terra Australis, but it was the British who permanently colonized the habitable southeastern coastal strip in 1788. One hundred years after the prisoners took their first steps on the beaches of Sydney and most of the original inhabitants had been pushed out or wiped out by guns and smallpox, the British brimmed with optimism about the country’s future. That made sense: the American colonies were thriving, albeit a little too well for British tastes, and the Australian continent was just as large as America. In 1888, a story in the Spectator sounded like a proud mother talking about her child’s future, with only a hint of racism, sexism, and disdain for Americans: “There is every reasonable probability that in 1988 Australia will be a Federal Republic, peopled by 50 millions of English speaking men, who, sprung from the same races as the Americans of the Union, will have developed a separate and recognisable type. . . . The Australians, we conceive, with more genial and altogether warmer climate, without Puritan traditions, with wealth among them from the first . . . will be a softer, though not a weaker people, fonder of luxury, and better fitted to enjoy art . . . The discontent which permeates the whole American character will be absent and, if not exactly happier, they will be more at ease. The typical Australian will be a sunnier man.” “Topics of the Day: The Next Centenary of Australia,” Spectator 61 (January 28, 1888): 112–13.
Though the prediction about Australian male sunniness and relative paucity of Puritanism was spot on, it was off on its math. After 1888, Australia’s population grew less than half as fast as predicted, in large part due to the absence of arable land. In 2018, the country had a population of only 25 million. But most Australians disagree with Sheridan, even more so after a few beers. They believe that the country is already overcrowded and the land is nearing its carrying capacity. Calls to limit immigration have dominated conversations, talk shows, and politics for three decades, long before it was fashionable in the United States. Many are deeply angry about the ever-increasing housing costs and commuting times. Some are simply racist. Others are professional scaremongers. Ted Trainer, Australia’s answer to Paul Ehrlich, has been arguing his whole career that levels of human consumption and resource use are already unsustainable. I know because I took his university course in 1988. According to Trainer, gasoline would run out before the 2000s and we were all supposed to be starving by now. Trainer’s version of utopia is his alternative-lifestyle, unkempt educational farm an hour’s drive south of Sydney, called Pigface Point. I spent a day there, learning by example, for example, that to save the world we needed to start living on three-acre farms, use solar-powered ovens to cook homegrown eggs, and commute an hour each way in a rusty, smoke-belching car to give lectures on green living. Yes, we have major issues to solve—climate change being the most threatening. But contrary to Trainer’s teachings, technology is not the enemy. In the arc of human history, technology has ultimately come to our rescue. For most of us, our daily life is improving, and it will continue to improve, just as London in 1840 and New York in 1900 did. There are more people than ever in the cities of North America, Europe, and Australasia, but today the impact of each human is rapidly declining and, contrary to what I was taught in the 1980s about the future, cities are getting cleaner. We’re moving from petroleum to natural gas to solar and electricity. A visit to Bangkok used to provoke respiratory distress. Now there’s blue sky. When I arrived in Boston in 1995, a splash of water from the harbor could land you in the hospital or the grave. Now it is safe for swimming.
53. E. C. Ellis, “Overpopulation Is Not the Problem,” New York Times, September 13, 2013, https://www.nytimes.com/2013/09/14/opinion/overpopulation-is-not-the-problem.html.
54. “World Population Projections,” Worldometers, http://www.worldometers.info/world-population/world-population-projections/.
55. Ibid. and Population Division, Department of Economic and Social Affairs, United Nations Secretariat, “2017 Revision of World Population Prospects,” https://population.un.org/wpp/.
56. Gates’s argument is simple enough: when you improve children’s health so they don’t die at an early age, families choose to have fewer children. B. Gates, “Does Saving More Lives Lead to Overpopulation?,” YouTube, February 13, 2018, https://www.youtube.com/watch?v=obRG-2jurz0.
57. The others were Denmark, Finland, Norway, Great Britain, Germany, and France. M. Roser, “Share of the Population Who Think the World Is Getting Better,” Our World in Data, https://ourworldindata.org/wp-content/uploads/2016/12/Optimistic-about-the-future-2.png.
58. The Guardian asked, “To what extent, if at all, do you feel that today’s youth will have had a better or worse life than their parent’s [sic] generation?” Though the Chinese polled were optimistic for the future of their youths, only 20 percent in the United Kingdom thought things will be better for future young people, with 54 percent expecting them to get worse. The poll was taken in the face of rising rents, house prices, and university fees in Great Britain, together with a steep drop in wages, which had in turn driven austerity policies. S. Malik, “Adults in Developing Nations More Optimistic than Those in Rich Countries,” Guardian, April 14, 2014, https://www.theguardian.com/politics/2014/apr/14/developing-nations-more-optimistic-richer-countries-survey.
59. In developing countries, which may well still have high child mortality rates, they nevertheless are also seeing declines in numbers. Our World in Data’s Max Roser pointed out that in sub-Saharan Africa child mortality has dropped consistently over the past fifty years; whereas it was one in four in the 1960s, it’s now one in ten. M. Roser, “Child Mortality,” Our World in Data, https://ourworldindata.org/child-mortality.
60. Steven Pinker, Enlightenment Now: The Case for Reason, Science, Humanism, and Progress (New York: Viking, 2018), 51.
61. Among her many charms, gifts, and abilities, there was also a dry, self-deprecating wit. At a luncheon for women executives shortly before her death, Thompson said about what was her last marathon, “I didn’t get much attention, even though I was coming in first—I was the only one in my age group.” R. Sandomir, “Harriette Thompson, Marathon Runner into Her 90s, Dies at 94,” New York Times, October 19, 2017, https://www.nytimes.com/2017/10/19/obituaries/harriette-thompson-dead-ran-marathons-in-her-90s.html.
62. “Old Age: Personal Crisis, U.S. Problem,” Life, July 13, 1959, pp. 14–25.
63. The price that older unemployed workers pay for this discrimination is harsh. AARP writer Nathaniel Reade laid out a few of the statistics: “Forty-four percent of jobless workers 55 or older had been unemployed for over a year in 2012, a Pew study reported. And while older workers have a lower unemployment rate overall, the ones who lose their jobs can find the long hunt for work unbearable.” Many are forced to tap into their Social Security, which puts not only their benefits but a financially secure retirement at risk. N. Reade, “The Surprising Truth About Older Workers,” AARP The Magazine, September 2015, https://www.aarp.org/work/job-hunting/info-07-2013/older-workers-more-valuable.html.
64. That’s according to research by Fabrizio Carmignani, a professor of business at Griffith University in Australia. F. Carmignani, “Does Government Spending on Education Promote Economic Growth?,” The Conversation, June 2, 2016, https://theconversation.com/does-government-spending-on-education-promote-economic-growth-60229.
65. M. Avendano, M. M. Glymour, J. Banks, and J. P. Mackenbach, “Health Disadvantage in US Adults Aged 50 to 74 Years: A Comparison of the Health of Rich and Poor Americans with That of Europeans,” American Journal of Public Health 99, no. 3 (March 2009): 540–48, https://www.ncbi.nlm.nih.gov/pubmed/19150903.
66. Of all the European countries, the United Kingdom will have the oldest working population, having set the retirement age to rise to 69 by 2046. “Retirement in Europe,” Wikipedia, https://en.wikipedia.org/wiki/Retirement_in_Europe.
67. “Impact of Automation,” Life, July 19, 1963, 68–88.
68. A. Swift, “Most U.S. Employed Adults Plan to Work Past Retirement Age,” Gallup, May 8, 2017, http://news.gallup.com/poll/210044/employed-adults-plan-work-past-retirement-age.aspx?g_source=Economy&g_medium=lead&g_campaign=tiles.
69. Only 25 percent said they’d stop working altogether at retirement age, according to Gallup. Those who planned to work part-time after retirement age comprised 63 percent of those polled. Ibid.
70. In 2014, Massachusetts ranked fifth nationwide for the number of patents issued, having had an 81.3 percent increase over the prior ten years in patents issued to state inventors. E. Jensen-Roberts, “When It Comes to Patents, Massachusetts Is a Big Player,” Boston Globe, August 9, 2015, https://www.bostonglobe.com/magazine/2015/08/08/when-comes-patents-massachusetts-big-player/3AmNfmSE8xWzzNbUnDzvPK/story.html.
71. D. Goldman, “The Economic Promise of Delayed Aging,” Cold Spring Harbor Perspectives in Medicine 6, no. 2 (December 18, 2015): a025072, http://perspectivesinmedicine.cshlp.org/content/6/2/a025072.full.
72. The authors contend that “the social, economic, and health benefits that would result from such advances may,” in the same way a “peace dividend” enables countries to rise out of poverty, “be thought of as ‘longevity dividends,’ and that they should be aggressively pursued as the new approach to health promotion and disease prevention in the 21st century.” S. J. Olshansky, D. Perry, R. A. Miller, and R. N. Butler, “Pursuing the Longevity Dividend: Scientific Goals for an Aging World,” Annals of the New York Academy of Sciences 114 (October 2017): 11–13, https://www.ncbi.nlm.nih.gov/pubmed/17986572.
73. Though 0.1 percent might not sound like much of the global population, that’s still 7.8 million full-time researchers. “Facts and Figures: Human Resources,” UNESCO, https://en.unesco.org/node/252277.
74. If the experiment sounds vaguely familiar, perhaps it’s because its inspiration came from the 1964 murder of Kitty Genovese in Queens, New York. Her screams for help reached the ears of thirty-eight neighbors, but none tried to help her. I. Shenker, “Test of Samaritan Parable: Who Helps the Helpless?,” New York Times, April 10, 1971, https://www.nytimes.com/1971/04/10/archives/test-of-samaritan-parable-who-helps-the-helpless.html.
75. Seneca, the philosopher who lived from c. 5 BC to AD 65, wrote about the brevity of life, the art of living, and the importance of morality and reason. Seneca, On the Shortness of Life: Life Is Long if You Know How to Use It, trans. G.D.N. Costa, Penguin Books Great Ideas (New York: Penguin Books, 2004).
NINE. A PATH FORWARD
1. J. M. Spaight, Aircraft in War (London: Macmillan, 1914), 3.
2. This was one of what has become known as three “laws” penned by Clarke, each famous in its own right. The other two were “The only way of discovering the limits of the possible is to venture a little way past them into the impossible” and “Any sufficiently advanced technology is indistinguishable from magic.” A. C. Clarke, “Hazards of Prophecy: The Failure of Imagination,” in Profiles of the Future: An Inquiry into the Limits of the Possible (New York: Orion, 1962), 14, 21, 36
3. L. Gratton and A. Scott, The 100 Year Life: Living and Working in an Age of Longevity (London and New York: Bloomsbury Publishing, 2018).
4. “And the days of Isaac were an hundred and fourscore years. And Isaac gave up the ghost, and died, and was gathered unto his people, being old and full of days: and his sons Esau and Jacob buried him.” Genesis 35:28, King James Version.
5. It was initially funded by a clerk from the Treasury Department garnishing twenty cents a month from each merchant seaman’s wages to pay for a number of contract hospitals. “A Short History of the National Institutes of Health,” Office of NIH History, https://history.nih.gov/exhibits/history/index.html.
6. That’s according to the Buck Institute for Research on Aging, which also noted that “if we move outside academic research to money spent on commercialized research applications by private companies, the pie changes quite a bit. In aggregate, drug companies outspend the NIH on R&D every year by over $20 billion.” “Who funds basic aging research in the US?,” Fight Aging!, March 25, 2015, https://www.fightaging.org/archives/2015/03/who-funds-basic-aging-research-in-the-us/.
7. The authors highlight the looming crisis the globe faces in terms of the increasing number of aged. Come 2050, they estimate, the number of those over 60 will be just over 2 billion, five times the number they were a century before. And 1.5 billion will be from developing countries. L. Fontana, B. K. Kennedy, V. D. Longo, et al., “Medical Research: Treat Ageing,” Nature 511, no. 750 (July 23, 2014): 405–7, July 24, 2014, https://www.nature.com/news/medical-research-treat-ageing-1.15585.
8. “Estimates of Funding for Various Research, Condition, and Disease Categories (RCDC),” National Institutes of Health, May 18, 2018, https://report.nih.gov/categorical_spending.aspx.
9. R. Brookmeyer, D. A. Evans, L. Hebert, et al., “National Estimates of the Prevalence of Alzheimer’s Disease in the United States,” Alzheimer’s & Dementia 7, no. 1 (January 2011): 61–73, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3052294/.
10. The average American spends $1,100 on coffee every year. “2017 Money matters report,” Acorns, 2017, https://sqy7rm.media.zestyio.com/Acorns2017_MoneyMattersReport.pdf.
11. “Actuarial Life Table,” Social Security, 2015, https://www.ssa.gov/OACT/STATS/table4c6.html.
12. Looking back over his life in a wide-ranging interview with Nautilus’s Jordana Cepelewicz, Hayflick noted that what money was invested in aging research did not go to where he felt it should. Most studies of aging focus on longevity determinants or diseases linked to age, he said. “Less than 3 percent of the budget of the National Institute on Aging in the past decade or more has been spent on research on the fundamental biology of aging.” J. Cepelewicz, “Ingenious: Leonard Hayflick,” Nautilus, November 24, 2016, http://nautil.us/issue/42/fakes/ingenious-leonard-hayflick.
13. The film Gattaca is about a future society driven by eugenics in which children are genetically selected to ensure that they possess the best hereditary traits. A father asks the geneticist, “We were wondering if we should leave some things to chance.” The geneticist responds, “You want to give your child the best possible start. Believe me, we have enough imperfection built in already. Your child doesn’t need any additional burdens.” A. Nicols, director, Gattaca, 1997.
14. The authors calculated that “from 1970 to 2000, gains in life expectancy added about $3.2 trillion per year to national wealth, with half of these gains due to progress against heart disease alone.” A cure for cancer “would be worth about $50 trillion.” K. M. Murphy and R. H. Topel, “The Value of Health and Longevity,” Journal of Political Economy 114, no. 5 (October 2006): 871–904, https://ucema.edu.ar/u/je49/capital_humano/Murphy_Topel_JPE.pdf.
15. D. Goldman, B. Shang, J. Bhattacharya, and A. M. Garber, “Consequences of Health Trends and Medical Innovation for the Future Elderly,” Health Affairs 24, suppl. 2 (February 2005): W5R5–17, https://www.researchgate.net/publication/7578563_Consequences_Of_Health_Trends_And_Medical_Innovation_For_The_Future_Elderly.
16. For a good read, I recommend Bill Bryson’s books on this topic. Notes from a Big Country (UK)/I’m a Stranger Here Myself (USA), 1999; and Down Under, 2000, are my favorites.
17. A phrase often used by US politicians, from the Parable of Salt and Light in Jesus’s Sermon on the Mount. In Matthew 5:14, Jesus tells his listeners, “You are the light of the world. A city that is set on a hill cannot be hidden.”
18. It’s clearly impacting the workforce. The trend to live longer “is one factor contributing to a steady rise in the workforce participation rate of older Australians, especially women,” wrote Matt Wade in the Sydney Morning Herald. “About one in five Australian workers are now aged over 55 years, compared with less than one in 10 in the 1980s and 1990s.” M. Wade, “Trend for Australians to Live Longer Reshapes Economy,” Sydney Morning Herald, August 12, 2018, https://www.smh.com.au/business/the-economy/trend-for-australians-to-live-longer-reshapes-economy-20180810-p4zwuv.html?btis.
19. What does the phrase “Medicare for all” mean? According to a CNBC article, Reuters defines it as “a publicly financed, privately delivered system with all Americans enrolled and all medically necessary services covered.” Meanwhile, the cost of health care for US citizens keeps on climbing. “The average annual deductible for employer-sponsored health care plans, which make up most of the plans in the U.S., was $1,505 in 2017, compared to $303 in 2006,” according to the Kaiser Family Foundation, wrote Yoni Blumberg for CNBC Make It. Y. Blumberg, “70% of Americans Now Support Medicare-for-All—Here’s How Single-Payer Could Affect You,” CNBC Make It, August 28, 2018, https://www.cnbc.com/2018/08/28/most-americans-now-support-medicare-for-all-and-free-college-tuition.html.
20. “Australians Living Longer but Life Expectancy Dips in US and UK,” Guardian, August 16, 2018, https://www.theguardian.com/society/2018/aug/16/australians-living-longer-but-life-expectancy-dips-in-us-and-uk.
21. Indeed, Americans who live in the top-income counties enjoy on average twenty years more of life than those living in the poorest counties, wrote Senator Bernie Sanders, and that is at least partly due to what he termed “grossly unequal access to quality healthcare.” B. Sanders, “Most Americans Want Universal Healthcare. What Are We Waiting For?,” Guardian, August 14, 2017, https://www.theguardian.com/commentisfree/2017/aug/14/healthcare-a-human-right-bernie-sanders-single-payer-system.
22. In fact, the Patient Factor lists at the top of the world’s health care systems (courtesy of the World Health Organization) the following countries: (1) France, (2) Italy, (3) San Marino, (4) Andorra, (5) Malta. “World Health Organization’s Ranking of the World’s Health Systems,” The Patient Factor, http://thepatientfactor.com/canadian-health-care-information/world-health-organizations-ranking-of-the-worlds-health-systems/.
23. “My father says that America has the best healthcare system in the world. What can I say to prove him wrong?,” Quora, https://www.quora.com/My-father-says-that-America-has-the-best-healthcare-system-in-the-world-What-can-I-say-to-prove-him-wrong.
24. N. Hanauer, “The Pitchforks Are Coming . . . For Us Plutocrats,” Politico, July/August 2014, https://www.politico.com/magazine/story/2014/06/the-pitchforks-are-coming-for-us-plutocrats-108014.
25. See International Journal of Astrobiology, https://www.cambridge.org/core/journals/international-journal-of-astrobiology.
26. P. Dayal, C. Cockell, K. Rice, and A. Mazumdar, “The Quest for Cradles of Life: Using the Fundamental Metallicity Relation to Hunt for the Most Habitable Type of Galaxy,” Astrophysical Journal Letters, July 15, 2015, https://arxiv.org/abs/1507.04346.
27. “List of Nearest Terrestrial Exoplanet Candidates,” Wikipedia, https://en.wikipedia.org/wiki/List_of_nearest_terrestrial_exoplanet_candidates.
28. George Monbiot, “Cutting Consumption Is More Important Than Limiting Population,” “George Monbiot’s Blog,” Guardian, February 25, 2009, https://www.theguardian.com/environment/georgemonbiot/2009/feb/25/population-emissions-monbiot.
29. S. Pinker, Enlightenment Now: The Case for Reason, Science, Humanism, and Progress (New York: Penguin Random House, 2018), 333.
30. One home builder told CNBC reporter Diana Olick that young adults are reluctant to leave rental apartments decked out by owners to be “resortlike,” given that they can’t afford to buy an apartment with similar amenities. Olick found that younger Americans “seem to be drawn to smaller, simpler living,” citing the tiny-house trend, one underpinned by technology equipping small spaces with “big amenities.” D. Olick, “Why Houses in America Are Getting Smaller,” CNBC, August 23, 2016, https://www.cnbc.com/2016/08/23/why-houses-in-america-are-getting-smaller.html.
31. A $20 billion New York start-up called WeWork focuses on offering shared working environments rich with immediately accessible amenities. The eight-year-old business, at the time of David Gelles’s New York Times business profile, had “built a network of 212 shared working spaces around the globe” and was in the process of putting up the fifteen-story Dock 72 on the East River. Along with a vast coworking space, “there will be a juice bar, a real bar, a gym with a boxing studio, an outdoor basketball court and panoramic vistas of Manhattan. There will be restaurants and maybe even dry cleaning services and a barbershop.” D. Gelles, “The WeWork Manifesto: First, Office Space. Next, the World,” New York Times, February 17, 2018, https://www.nytimes.com/2018/02/17/business/the-wework-manifesto-first-office-space-next-the-world.html.
32. And let us not forget the water we expend on producing crops and meat that we never eat. 2013 estimates put the amount of water being used for food production by 2050 at 10 to 13 trillion cubic meters a year, which is 3.5 times as much as the amount of fresh water currently consumed by the planet’s population. J. von Radowitz, “Half of the World’s Food ‘Is Just Thrown Away,’ ” Independent, January 10, 2013, https://www.independent.co.uk/environment/green-living/half-of-the-worlds-food-is-just-thrown-away-8445261.html.
33. Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, “Scientists Engineer Shortcut for Photosynthetic Glitch, Boost Crop Growth 40%,” Science Daily, January 3, 2019, https://www.sciencedaily.com/releases/2019/01/190103142306.htm.
34. P. Mirocha, and A. Mirocha, “What the Ancestors Ate,” Edible Baja Arizona, September/October 2015, http://ediblebajaarizona.com/what-the-ancestors-ate.
35. J. Wenz, “The Mother of All Apples Is Disappearing,” Discover, June 8, 2017, http://blogs.discovermagazine.com/crux/2017/06/08/original-wild-apple-going-extinct/#.W_3i8ZNKjOQ.
36. “Vitamin A deficiency is the leading cause of preventable childhood blindness and increases the risk of death from common childhood illnesses such as diarrhoea,” according to a late-2017 UNICEF report. It stated that vitamin A had been shown to “reduce all-cause mortality by 12 to 24 percent, and is therefore an important programme in support of efforts to reduce child mortality.” “Vitamin A Deficiency,” UNICEF, February 2019, https://data.unicef.org/topic/nutrition/vitamin-a-deficiency/.
37. Luciano Marraffini and Erik Sontheimer at Northwestern University in Evanston, Illinois, were the first to show how CRISPR protects bacteria from foreign DNA: the interference machinery targets DNA directly. “From a practical standpoint, the ability to direct the specific, addressable destruction of DNA . . . could have considerable functional utility, especially if the system can function outside of its native bacterial or archaeal context,” they wrote. L. A. Marraffini and E. J. Sontheimer, “CRISPR Interference Limits Horizontal Gene Transfer in Staphylococci by Targeting DNA,” Science 322, no. 5909 (December 19, 2008): 1843–45, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2695655/; see also J. Cohen, “How the Battle Lines over CRISPR Were Drawn,” Science, February 17, 2017, https://www.sciencemag.org/news/2017/02/how-battle-lines-over-crispr-were-drawn.
38. M. R. O’Connell, B. L. Oakes, S. H. Sternberg, et al., “Programmable RNA Recognition and Cleavage by CRISPR/Cas9,” Nature 516, no. 7530 (December 11, 2014): 263–66, https://www.ncbi.nlm.nih.gov/pubmed/25274302.
39. L. Cong, F. A. Ran, D. Cox, et al., “Multiplex Genome Engineering Using CRISPR/Cas Systems,” Science 339, no. 6121 (February 15, 2013): 819–23, https://www.ncbi.nlm.nih.gov/pubmed/23287718.
40. Court of Justice of the European Union, “Organisms Obtained by Mutagenesis Are GMOs and Are, in Principle, Subject to the Obligations Laid Down by the GMO Directive,” July 25, 2018, https://curia.europa.eu/jcms/upload/docs/application/pdf/2018-07/cp180111en.pdf.
41. “Secretary Perdue Statement on ECJ Ruling on Genome Editing,” U.S. Department of Agriculture, July 27, 2018, https://www.usda.gov/media/press-releases/2018/07/27/secretary-perdue-statement-ecj-ruling-genome-editing.
42. LEDs are tiny, no larger than a fleck of pepper, and mixing primary-colored LEDs, i.e., red, green, and blue, results in white light. “LED Lighting,” Energy Saver, https://www.energy.gov/energysaver/save-electricity-and-fuel/lighting-choices-save-you-money/led-lighting.
43. In 2016, the City of Angels achieved an 11 percent emissions cut (the same as 737,000 cars coming off the streets) via an improved public transport system and solar energy investments, while creating “30,000 new green jobs,” wrote Matt Simon in Wired. M. Simon, “Emissions Have Already Peaked in 27 Cities—and Keep Falling,” Wired, September 13, 2018, https://www.wired.com/story/emissions-have-already-peaked-in-27-cities-and-keep-falling/.
44. It turned out that the source of the pollution was “problematic connections between the pipes that carried sewage and those that were meant to carry clean rainwater out to the river,” according to a Citylab story by Stephanie Garlock. When a rainstorm hit, “everything in the pipes, sewage and all, would flush directly into the Charles and its tributaries through older drainage pipes.” Renovations of the sewage systems have all but eradicated the problem. S. Garlock, “After 50 Years, Boston’s Charles River Just Became Swimmable Again,” Citylab, July 19, 2013, https://www.citylab.com/life/2013/07/after-50-years-bostons-charles-river-just-became-swimmable-again/6216/.
45. The farm cost 200 million Australian dollars to construct and has a solar plant made up of 23,000 mirrors that reflects the heat of the sun to a solar tower. Rather than soil, the tomato plants grow in “a watery solution fed by nutrient-rich coconut husks.” E. Bryce, “These Farms Use Sun and Seawater to Grow Crops in the Arid Australian Desert,” Wired, February 14, 2017, https://www.wired.co.uk/article/sundrop-farms-australian-desert. See also Sundrop Farms, http://www.sundropfarms.com.
46. Letter from Joseph Wharton, December 6, 1880, https://giving.wharton.upenn.edu/wharton-fund/letter-joseph-wharton/.
47. P. Sopher, “Where the Five-Day Workweek Came From,” Atlantic, August 21, 2014, https://www.theatlantic.com/business/archive/2014/08/where-the-five-day-workweek-came-from/378870/.
1. E. Pesheva, “Rewinding the Clock,” Harvard Medical School, March 22, 2018, https://hms.harvard.edu/news/rewinding-clock; see also A. Das, G. X. Huang, M. S. Bonkowski, et al., “Impairment of an Endothelial NAD+-H2S Signaling Network Is a Reversible Cause of Vascular Aging,” Cell 173, no. 1 (March 2018): 74–89, https://www.sciencedirect.com/science/article/pii/S0092867418301521.
2. J. Li, M. S. Bonkowski, S. Moniot, et al., “A conserved NAD+ Binding Pocket That Regulates Protein-Protein Interactions During Aging,” Science 355, no. 6331 (March 24, 2017): 1312–17, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5456119/.
3. President’s Council on Bioethics, Beyond Therapy: Biotechnology and the Pursuit of Happiness (New York: HarperCollins, 2003), 190.
4. Ibid., 192.
5. Ibid., 200.
6. “ICD-11 for Mortality and Morbidity Statistics: MG2A Old Age,” World Health Organization, December 2018, https://icd.who.int/browse11/l-m/en#/http://id.who.int/icd/entity/835503193.
7. Bravo Probiotic Yogurt, https://www.bravo-probiotic-yogurt.com/.
8. Y. Guan, S.-R. Wang, X.-Z. Huang, et al., “Nicotinamide Mononucleotide, an NAD+ Precursor, Rescues Age-Associated Susceptibility to AKI in a Sirtuin 1–Dependent Manner,” Journal of the American Society of Nephrology 28, no. 8 (August 2017): 2337–52, https://jasn.asnjournals.org/content/28/8/2337; see also S. Wakino, K. Hasegawa, and H. Itoh, “Sirtuin and Metabolic Kidney Disease,” Kidney International 88, no. 4 (June 17, 2015): 691–98, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4593995/.
