by Bill Gifford
3. “a bunch of tiny jabs”: M. Ito et al. (2007). “Wnt-dependent de novo hair follicle regeneration in adult mouse skin after wounding.” Nature 447(7142): 316-320.
4. “to make room for the next generation”: The evolution of aging is discussed in several articles, and books, but one of the better summaries (particularly of Weissmann’s theory) is Michael R. Rose et al. (2008), “Evolution of Ageing since Darwin,” Journal of Genetics, 87, 363–371; the same subject is treated in D. Fabian and T. Flatt (2011) “The Evolution of Aging,” in Nature Education Knowledge 3(10):9.
5. “The idea of group-based selection”: Some theorists have revived the idea that our aging might serve some sort of evolutionary purpose—in particular, population control. One fact that has been widely observed is that an abundance of food actually makes most animals more likely to die young. This holds true up and down the tree of life, from single-celled organisms all the way up to the people you see in Walmart. Could that be some sort of mechanism to keep us, and things like locusts, from overpopulating the earth and eating everything in sight? Perhaps. Although for 99 percent of human history, this has not been a problem.
6. “What struck Haldane as odd”: J. B. S. Haldane, “The Relative Importance of Principal and Modifying Genes in Determining Some Human Diseases,” in New Paths in Genetics. London, G. Allen & Unwin Ltd. 1941.
7. “the fact that white people get tan”: Zeron-Medina et al. “A Polymorphic p53 Response Element in KIT Ligand Influences Cancer Risk and Has Undergone Natural Selection.” Cell 155(2): 410-422.
8. “a gene called daf-2”: C. Kenyon, J. Chang, E. Gensch, A. Rudner, R. Tabtiang (1993). “A C. elegans mutant that lives twice as long as wild type,” Nature 366 (6454): 461–464. Kenyon later described the process of discovery in C. Kenyon, (2011). “The first long-lived mutants: discovery of the insulin/IGF-1 pathway for ageing.” Philosophical Transactions of the Royal Society B: Biological Sciences 366(1561): 9-16.
9. “the long-lived worms were all but extinct”: Nicole L. Jenkins et al., “Fitness cost of increased lifespan in C. elegans,” Proceedings of the Royal Society London B (2004) 271, 2523–2526.
10. “before the advent of birth control”: V. Tabatabaie et al. (2011). “Exceptional longevity is associated with decreased reproduction.” Aging (Albany NY) 3(12): 1202-1205.
11. “time to find a new line of work”: Austad recounted his dealings with Orville (and the possums) in “Taming Lions, Unleashing a Career,” Science Aging Knowledge Environment, 27 March 2002, Issue 12, p. vp3.
12. “the ‘disposable soma’ theory”: Kirkwood explains his theory, and much else about aging, in his excellent book Time of Our Lives: The Science of Human Aging (New York: Oxford University Press, 1999). The original “disposable soma” paper is at T. B. Kirkwood, Evolution of ageing. 1977. Nature 170(5635) 201-4. In more recent years the theory has come under attack for various shortcomings, but few scientists disagree with its big-picture conclusion, that lifespan and reproduction exist in a delicate balance.
13. “The clam, nicknamed Ming”: Ming’s discovery was reported in this very dry paper on oceanography (by Paul Butler and others) titled “Variability of marine climate on the North Icelandic Shelf in a 1357-year proxy archive based on growth increments in the bivalve Arctica islandica.” Palaeogeography, Palaeoclimatology, Palaeoecology Volume 373, 1 March 2013, pages 141–151; her (his?) death was widely reported, e.g., in “New Record: World’s Oldest Animal was 507 Years Old,” by Lise Brix, ScienceNordic.com, November 6, 2013.
14. “what he calls Methuselah’s Zoo”: S. N. Austad, “Methuselah’s Zoo: How Nature provides us with clues for extending human healthspan,” in Journal of Comparative Pathology, 2010 January; 142(Suppl 1): S10–S21.
15. “bat cells withstood stress”: A. B. Salmon et al. (2009). “The long lifespan of two bat species is correlated with resistance to protein oxidation and enhanced protein homeostasis.” Journal of the Federation of American Societies of Experimental Biology 23(7): 2317-2326.
Chapter 8: The Lives of Our Cells
1. “No one dared question his work”: J. A. Witkowski, “Alexis Carrel and the Mysticism of Tissue Culture,” Medical History, 1979, 23: 279-296. More recent historians have been a bit less condemnatory of Carrel, who had some good ideas along with the bad.
2. “Far from being immortal”: L. Hayflick, “The Limited in vitro Lifetime of Human Diploid Cell Strains,” Experimental Cell Research 67: 614-36 (1965).
3. “WI-38 proved to be the most durable and useful cell line”: The story of Hayflick and WI-38, and his role in the science of tissue culture, is told very well by journalist Meredith Wadman in “Medical Research: Cell Division,” Nature 498, 422–426 (27 June 2013). Hayflick’s settlement with the government was described by Philip Boffey, “The Fall and Rise of Leonard Hayflick, Biologist whose Fight With U.S. Seems Over,” New York Times, January 19, 1982.
4. “the center of the abortion controversy”: The Vatican’s objections were summarized here: http://www.immunize.org/concerns/vaticandocument.htm. Many fundamentalist Christians still refuse certain vaccinations on these grounds.
5. “his assistants had been replenishing them”: L. Hayflick, interview, March 1, 2013; for further treatment of Carrel’s influence on the study of aging, see H. W. Park, (2011), “ ‘Senility and death of tissues are not a necessary phenomenon’: Alexis Carrel and the origins of gerontology.” Uisahak 20(1): 181-208.
6. “These telomeres, as they were called”: The telomeres-telomerase story is well retold by Carol Greider in “Telomeres and senescence: The history, the experiment, the future,” Current Biology Vol 8, Issue 5, 26 February 1998, pages R178–R181.
7. “telomere length and overall mortality”: “A. L. Fitzpatrick, R. A. Kronmal, M. Kimura, J. P. Gardner, B. M. Psaty et al. (2011)Leukocyte telomere length and mortality in the Cardiovascular Health Study.” Journals of Gerontology A: Biological Sciences/Medical Science 66: 421–429; Also E. S. Epel et al. (2004). “Accelerated telomere shortening in response to life stress.” Proceedings of the National Academy of Sciences 101(49): 17312-17315.
8. “if you control for unhealthy behaviors”: M. Weischer et al. (2014). “Telomere shortening unrelated to smoking, body weight, physical activity, and alcohol intake: 4,576 general population individuals with repeat measurements 10 years apart.” PLoS Genetics 10(3): e1004191.
9. “a widely publicized study”: Mariela Jaskelioff et al., “Telomerase reactivation reverses tissue degeneration in aged telomerase deficient mice,” Nature 2011 January 6; 469(7328): 102–106.
10. “more liver tumors than the control mice”: Bruno Bernardes de Jesus et al., “The telomerase activator TA-65 elongates short telomeres and increases health span of adult /old mice without increasing cancer incidence,” Aging Cell (2011) 10, 604–621. Despite the title, the mice treated with TA-65 were 30 percent more likely to develop lymphoma and cancer in their livers (p. 615), but because the study involved just 36 animals in total, the finding was deemed not statistically significant by the authors.
11. “the twenty-five-year-long Rancho Bernardo study”: J. K. Lee et al. (2012). “Association between Serum Interleukin-6 Concentrations and Mortality in Older Adults: The Rancho Bernardo Study.” PLoS One 7(4): e34218.
12. “nestled against a Marin County hillside”: Heading north from San Francisco on U.S. 101, look to your left just past the exit for Novato, and you’ll see the Buck Institute up on the hill. Easily the most spectacular research institute I’ve ever seen, but in 2013 it was nearly bankrupted by lawsuits from creditors of the defunct Lehman Brothers investment firm. (Long story: “Lehman Reaches from beyond Grave Seeking Millions from Nonprofits,” by Martin Z. Braun, Bloomberg.com, May 24, 2013.)
13. “the senescence-associated secretory phenotype”: This is one of the most important concepts in cellular aging, and it has been found to have broad implications for physiology and health. Campisi’s original SASP paper is here: J. P. Coppe et al. (
2008). “Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor.” PLoS Biology 6(12): 2853-2868. For less thorny reading, try J. Campisi et al. (2011), “Cellular senescence: a link between cancer and age-related degenerative disease?” Seminars in Cancer Biology 21(6): 354-359. Or better yet, search on YouTube for “Senescent cells Campisi”—she’s a very good speaker.
14. “patients who had been treated for HIV”: The observed rapid aging of the drug-treated HIV population raises its own issues, but has also shed insight on the nature of the aging process itself, in particular the relationship of the immune system to overall aging. J. B. Kirk and M. B. Goetz (2009), “Human immunodeficiency virus in an aging population, a complication of success,” Journal of the American Geriatrics Society 57(11): 2129-2138.
15. “senescent-cell-zapping drug”: The original paper is available free on the Nature website: D. J. Baker et al. (2011), “Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders,” Nature 479(7372): 232-236. For a simpler account, try “Cell-Aging Hack Opens Longevity Research Frontier,” by Brandon Keim, Wired.com, November 2, 2011.
Chapter 9: Phil vs. Fat
1. “Waist circumference also expands”: Waist circumference, also known as your waist size, is one of the most important “biomarkers” there is, far more important than BMI; numerous studies have linked waist circumference of more than 1 meter (in men) to all kinds of poor health outcomes (for women, the threshold is more like 36 inches). As a rule, your waist should be less than one-half your height: M. Ashwell et al. (2014), “Waist-to-height ratio is more predictive of years of life lost than body mass index,” PLoS One 9(9): e103483.
2. “very high end of ‘normal’ ”: Body-fat percentage ranges are from the American Council on Exercise: http://www.acefitness.org/acefit/healthy-living-article/60/112/what-are-the-guidelines-for-percentage-of/. Note that these are only averages; some sports scientists advocate still lower levels for both men and women, depending on what sport they pursue. http://www.humankinetics.com/excerpts/excerpts/normal-ranges-of-body-weight-and-body-fat.
3. “14 percent of cancer deaths in men”: E. E. Calle, C. Rodriguez, K. Walker-Thurmond, M. J. Thun. “Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults.” New England Journal of Medicine 2003 Apr 24;348(17):1625-38. Subsequent research has muddied the issue a bit, with some studies concluding that the ideal weight, mortality-wise, is somewhere around BMI of 25, on the edge of overweight; but while it may be better to be slightly overweight than underweight, more studies show that outright obesity is always associated with higher risk of disease and death.
4. “taking in just ten more calories”: The Lancet report also explained why it then becomes so hard to lose weight, because a successful diet requires cutting back by 250 calories per day, or more. (Good-bye, Hershey bar in the afternoon.) Kevin D. Hall et al., “Quantification of the effect of energy imbalance on bodyweight,” Lancet, Volume 378, Issue 9793, pp. 826–837, 27 August 2011.
5. “The fat is the problem.”: One huge study found that even for people of normal weight, excess visceral fat increased their risk of death. More cheery reading for you: T. Pischon et al. (2008), “General and Abdominal Adiposity and Risk of Death in Europe,” New England Journal of Medicine 359(20): 2105-2120.
6. “Not all fat is just fat”: This is one of my favorite studies ever: Researchers cut out the animals’ visceral fat, and they lived lots longer. R. Muzumdar et al. (2008), “Visceral adipose tissue modulates mammalian longevity,” Aging Cell 7(3): 438-440.
7. “only about half of diabetic patients”: In fairness, more patients are being told to exercise by their doctors; percentages increased from 2000 to 2010 across all categories and age groups. But half is still not everyone, and exercise has been shown to be the most powerful intervention against diabetes. Patricia Barnes, National Center for Health Statistics Data Brief no. 86, February 2012. http://www.cdc.gov/nchs/data/databriefs/db86.pdf.
8. “A. B. was a twenty-seven-year-old Scotsman”: W. K. Stewart and Laura W. Fleming, “Features of a Successful Therapeutic Fast of 382 Days’ Duration,” Postgraduate Medical Journal, March 1973; 49(569): 203–209. Maybe my second-favorite study. More recently, the evolutionary biologist John Speakman used a model of total starvation to call into question the “thrifty gene hypothesis,” which says that all humans are predisposed to obesity; why, he asked, are we therefore not all fat? J. R. Speakman and K. R. Westerterp (2013), “A mathematical model of weight loss under total starvation: evidence against the thrifty-gene hypothesis,” Disease Models & Mechanisms 6(1): 236-251.
Chapter 10: Pole Vaulting into Eternity
1. “to find out just what it is”: John Jerome, Staying With It (New York: Viking, 1984), 219. Jerome died in 2002, at age 70, of lung cancer.
2. “They were miraculously rejuvenated.”: Langer’s experiment was never published, except as a chapter in an obscure book; the results were too far out of the mainstream for 1981. In 2010, it was the basis of a BBC special, featuring aging celebrities. Langer was the subject of a recent New York Times Magazine profile, “The Thought That Counts,” by Bruce Grierson, October 26, 2014.
3. “the equivalent of a brisk walk”: S. C. Moore et al. (2012). “Leisure time physical activity of moderate to vigorous intensity and mortality: a large pooled cohort analysis.” PLoS Medicine 9(11): e1001335. There is a raging debate over how much exercise constitutes “too much,” fueled by numerous studies by James O’Keefe, a cardiologist in Kansas City, who argues that long-term endurance exercise delivers proportionally fewer benefits, and at the cost of possible damaging changes to the heart (e.g., J. H. O’Keefe et al. (2012). “Potential adverse cardiovascular effects from excessive endurance exercise.” Mayo Clinic Proceedings 87(6): 587-595. For most Americans, however, the problem is not too much exercise, but too little.
4. “just as effective as the medications”: Huseyin Naci and John Ioannidis, “Comparative effectiveness of exercise and drug interventions on mortality outcomes: metaepidemiological study.” BMJ 2013;347:f5577 (published 1 October 2013).
5. “National records also bear this out”: See www.mastersrankings.com.
6. “Even retiring from working”: Dhaval Dave, Inas Rashad, and Jasmina Spasojevic, “The Effects of Retirement on Physical and Mental Health Outcomes,” NBER Working Paper No. 12123. March 2006, January 2008. JEL No. I1, J0. http://www.nber.org/papers/w12123.
7. “because of something that circulates in old blood”: Irina M. Conboy et al., “Rejuvenation of aged progenitor cells by exposure to a young systemic environment.” Nature 433, 760-764 (17 February 2005). There will be lots more on the fascinating science of parabiosis later in the book.
8. “a male named Charlie”: Charlie won something called the “Reversal Prize,” awarded by the Methuselah Foundation for the longest extension of lifespan of a mouse. His handler, Sandy Keith, was awarded the prize in 2004. NIA scientist Mark Mattson has questioned whether standard captivity conditions, where mice have unlimited access to food but no chance to exercise or socialize, have skewed study results by making the mice unhealthy: B. Martin, S. Ji, S. Maudsley, and M. P. Mattson, “ ‘Control’ Laboratory Rodents Are Metabolically Morbid: Why It Matters,” Proceedings of the National Academy of Sciences USA 107, no. 14 (April 6 2010): 6127-33.
9. “more than 5.3 million premature deaths each year”: I. M. Lee et al. (2012), “Effect of physical inactivity on major non-communicable diseases worldwide: an analysis of burden of disease and life expectancy,” Lancet 380(9838): 219-229. Other scientists have picked up the ball, describing inactivity itself as a disease or, better, a dangerous activity on par with smoking. B. K. Pedersen (2009). “The diseasome of physical inactivity—and the role of myokines in muscle–fat cross talk,” The Journal of Physiology 587(23): 5559-5568.
10. “The primary signaling factor they identified”: B. K. Pedersen and M. A.
Febbraio, “Muscles, exercise and obesity: skeletal muscle as a secretory organ,” Nature Reviews Endocrinology, advance online publication April 3, 2012.
11. “analyzed the ‘gene expression’ patterns: Simon Melov, et al., “Resistance Exercise Reverses Aging in Human Skeletal Muscle,” PLoS ONE 2(5): e465. Tarnopolsky’s subsequent paper, looking at mitochondrial DNA mutation in mice, and its reversal through exercise, is at A. Safdar et al. (2011), “Endurance exercise rescues progeroid aging and induces systemic mitochondrial rejuvenation in mtDNA mutator mice,” Proceedings of the National Academy of Sciences 108(10): 4135-4140.
12. “Within eight generations, they found distinct differences”: M. D. Roberts et al. (2014), “Nucleus accumbens neuronal maturation differences in young rats bred for low versus high voluntary running behaviour,” Journal of Physiology 592(Pt 10): 2119-2135.
13. “A little bit of walking kept many of them out of the nursing home”: M. Pahor, J. M. Guralnik, W. T. Ambrosius et al., “Effect of Structured Physical Activity on Prevention of Major Mobility Disability in Older Adults: The LIFE Study Randomized Clinical Trial,” JAMA. 2014;311(23):2387-2396.
Chapter 11: Starving for Immortality
1. “He titled it Discorsi della vita sobria”: My edition, purchased online, was titled simply How to Live Long (New York: Health Culture, 1916).
2. “McCay’s resulting paper”: C. M. McCay, and Mary Crowell, (1935), “The effect of retarded growth upon the length of life span and upon the ultimate body size,” Nutrition 5(3): 155-171. A classic.
3. “McCay’s own special recipe for rat chow”: For more details on Clive McCay’s very interesting life, see his wife Jeanette’s autobiography, Clive McCay, Nutrition Pioneer: Biographical Memoirs by His Wife (Charlotte Harbor, FL: Tabby House, 1994). Also helpful was a doctoral dissertation by historian Hyung Wook Park (2010), “Longevity, aging, and caloric restriction: Clive Maine McCay and the construction of a multidisciplinary research program.” Historical Studies in the Natural Sciences 40(1): 79-124.