by Bill Gifford
4. “you could accomplish all kinds of things in this world”: The trailer for Rowland’s documentary on Walford, Signposts of Dr. Roy Walford, is at www.youtube.com/watch?v=K-PzhyTlODc.
5. “caloric restriction might actually be slowing the aging process itself”: Their seminal paper is R. Weindruch, and R. L. Walford (1982), “Dietary restriction in mice beginning at 1 year of age: effect on life-span and spontaneous cancer incidence,” Science 215(4538): 1415-1418. They later wrote a whole book about caloric restriction that you probably do not want to read.
6. “which still strikes Finch as ‘statistically unlikely.’ ”: Walford’s good friend Caleb Finch penned a biographical remembrance, “Dining With Roy,” Experimental Gerontology 39 (2004) 893–894), from which some of these details are drawn. Still more come from recollections kindly shared by both Finch and Rick Weindruch.
7. “Funded by the eccentric oil heir Ed Bass”: Good retrospective feature on Biosphere 2 by Tiffany O’Callaghan, “Biosphere 2: Saving the world within a world,” New Scientist, July 31, 2103.
8. “The supply of bananas, the tastiest item on the menu”: Many details about life inside Biosphere come from Jane Poynter, The Human Experiment: Two Years and Twenty Minutes Inside Biosphere 2 (New York: Basic Books, 2009).
9. “they had the best blood he had ever seen”: R. L. Walford et al. (1992) “The calorically restricted low-fat nutrient-dense diet in Biosphere 2 significantly lowers blood glucose, total leukocyte count, cholesterol, and blood pressure in humans,” Proceedings of the National Academy of Sciences 89(23): 11533-11537. The Biosphere came closest to fulfilling the suggestion, of a former director of the National Institute on Aging, that caloric restriction be studied (forcibly) on prisoners.
10. “Walford fell into a deep depression”: The gruesome aftermath of the Biosphere, for Walford at least, is recounted rather clinically in a paper by some of his colleagues: B. K. Lassinger, C. Kwak, R. L. Walford, and J. Jankovic (2004), “Atypical parkinsonism and motor neuron syndrome in a Biosphere 2 participant: A possible complication of chronic hypoxia and carbon monoxide toxicity?” Movement Disorders, 19: 465–469.
11. “he touted the benefits of caloric restriction to Alan Alda”: The man did not look well: www.youtube.com/watch?v=9jvqNG1g62Y.
12. “These genes, dubbed sirtuins”: The sirtuin-discovery story is well recounted by Guarente himself in Ageless Quest: One Scientist’s Search for Genes That Prolong Youth. (Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press, 2003).
13. “they were fitter, faster, and lots better-looking”: J. A. Baur et al. (2006), “Resveratrol improves health and survival of mice on a high-calorie diet,” Nature 444(7117): 337-342. The study made the Times front page with the headline, “Yes, Red Wine Holds Answer. Check Dosage,” by Nicholas Wade, November 2, 2006.
14. “those who consume red wine”: The literature on red wine is fascinating, even inspiring; multiple large European studies have shown huge health benefits associated with red wine consumption, and not just the one or two glasses per day that American doctors recommend, but more like three. J. P. Broustet, “Red Wine and Health,” Heart 1999;81:459-460.
15. “He hadn’t given up”: In 2014 Sinclair reported results of a new chemical sirtuin activator, which seemed to work even better than resveratrol. The unfortunate part is that the chemical, nicotine mononucleotide, currently costs about a thousand bucks per gram. Brace yourself: P. Ana Gomes et al. (2013), “Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging,” Cell 155(7): 1624-1638.
16. “decades younger than their chronological age”: Fontana’s results with the “Cronies” (Caloric Restriction with Optimal Nutrition), including Dowden, have been reported and analyzed in a long series of studies, beginning with L. Fontana et al., “Long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans.” Proceedings of the National Academy of Sciences 2004 April 7; 101(17):6659-63.
17. “The hungry monkeys were far healthier”: R. J. Colman et al. (2009), “Caloric restriction delays disease onset and mortality in rhesus monkeys,” Science 325(5937): 201-204.
18. “the ‘dieting’ monkeys had not lived longer”: J. A. Mattison et al. (2012), “Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study,” Nature 489(7415): 318-321. For a more readable commentary, published at the same time, see Steven Austad, “Mixed Results for Dieting Monkeys,” Nature (same issue).
19. “close to an institutional disaster”: Although it had become almost dogma that CR would extend lifespan all the time, there had been anomalous CR results in the past. Steven Austad had tried it in actual wild mice, captured in a barn in Idaho, rather than the usual, genetically-standardized laboratory mice. It had minimal effect on their lifespans. In another, more structured study, Jim Nelson of the University of Texas tried it in 40 different cross-bred mouse strains, and found that in a third of the breeds, dietary restriction actually shortened their lives. So clearly, it doesn’t work for everyone all the time. Even monkeys.
20. “better to be a little bit overweight”: The relationship of BMI to longevity (or mortality) is the subject of yet another thorny, contentious debate. It’s called the “obesity paradox,” the observation that being slightly overweight and even mildly obese is actually associated with living slightly longer—not only for the population as a whole, but for people who actually have hypertension and diabetes. It would take pages to unpack this, but the latest salvo appears to discredit the “paradox,” showing that being obese and diabetic (which the Wisconsin monkeys certainly were) is not good: D. K. Tobias et al. (2014), “Body-Mass Index and Mortality among Adults with Incident Type 2 Diabetes,” New England Journal of Medicine 370(3): 233-244.
21. “it’s not surprising they had different outcomes”: Not to be defeated, the Wisconsin team came back with a paper exploring, in detail, the many subtle differences that may have led to the drastically different outcomes of the two studies, not only diet but also the genetic background of the monkeys, their age when the respective studies were started, etc. R. J. Colman et al. (2014), “Caloric restriction reduces age-related and all-cause mortality in rhesus monkeys,” Nature Communications 5: 3557. If that’s still not enough for you, dive into Michael Rae’s exhaustive exegesis, “CR in Nonhuman Primates: A Muddle for Monkeys, Men, and Mimetics,” posted at www.sens.org on May 6, 2013. If nothing else, you will appreciate the extent to which the Whole Foods (NIH) Monkeys turned the field on its ear.
Chapter 12: What Doesn’t Kill You
1. “His essay about cold-water showering”: http://gettingstronger.org/2010/03/cold-showers/. Remember, the first minute is the worst.
2. “cold water might help increase their longevity”: For a readable overview on nematode worms and cold, see B. Conti and M. Hansen (2013), “A cool way to live long,” Cell 152(4): 671-672.
3. “After months of regular cold swimming”: A. Lubkowska et al. (2013), “Winter-swimming as a building-up body resistance factor inducing adaptive changes in the oxidant/antioxidant status,” Scandinavian Journal of Clinical and Laboratory Investigations, March 20, 2013 [epub ahead of print]. Think about this before you chicken out of that cold shower. Katharine Hepburn’s year-round swimming was documented by her biographer Charles Higham, in Kate: The Life of Katharine Hepburn (New York: W. W. Norton, 2004 [First published 1975]). HTFU.
4. “exposure to cold water could activate brown fat”: Paul Lee et al. “Irisin and FGF21 Are Cold-Induced Endocrine Activators of Brown Fat Function in Humans,” Cell Metabolism, Volume 19, Issue 2, 4 February 2014, 302-309.
5. “small doses of heat are also beneficial”: There is an extensive literature on heat-shock proteins, but one of the first to connect the heat-shock response, and indeed the concept of hormesis itself, to longevity was Suresh I. Rattan, in a review that garnered an extremely hostile response but is now widely accepted: S. I. Rattan, “Applying
hormesis in aging research and therapy,” Human & Experimental Toxicology. 2001 Jun;20(6):281-5; discussion 293-4.
6. “people who were lonely”: S. W. Cole et al. (2007), “Social regulation of gene expression in human leukocytes,” Genome Biology 8(9): R189.
7. “Free radicals flashed through my mind”: “An Interview with Dr. Denham Harman,” Life Extension, February 1998.
8. “Antioxidants didn’t really seem to extend lifespan”: For an excellent breakdown of this subject, see “The Myth of Antioxidants,” by Melinda Wenner Moyer, Scientific American 308, 62-67 (2013); published online January 14, 2013.
9. “antioxidant supplements have had a mixed track record”: G. Bjelakovic et al. (2007), “Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: Systematic review and meta-analysis,” JAMA 297(8): 842-857.
10. “worse than useless”: The supplements-in-exercise study is at M. Ristow, “Antioxidants prevent health-promoting effects of physical exercise in humans.” Proceedings of the National Academy of Sciences of the USA 106: 8665–8670, 2009. Ristow and others review that and similar studies (with mixed results) in Mari Carmen Gomez-Cabrera et al., “Antioxidant supplements in exercise: worse than useless?” American Journal of Physiology—Endocrinology and Metabolism 15 February 2012 Vol. 302no. E476-E477.
11. “essential signaling molecules”: M. Ristow, and S. Schmeisser (2011), “Extending life span by increasing oxidative stress,” Free Radical Biology in Medicine 51(2): 327-336. Also see M. Ristow (2014), “Unraveling the truth about antioxidants: mitohormesis explains ROS-induced health benefits,” Nature Medicine 20(7): 709-711.
12. “they rarely if ever see the sun”: Don’t miss the fantastic essay about the naked mole rat by Eliot Weinberger in Karmic Traces, 1993-1999 (New York: New Directions Publishing, 2000).
13. “they are better designed to handle stress”: K. N. Lewis et al. (2012). “Stress resistance in the naked mole-rat: the bare essentials—a mini-review.” Gerontology 58(5): 453-462. A good place to start, and my favorite bad-pun journal article title ever. Also see Y. H. Edrey et al. (2011), “Successful aging and sustained good health in the naked mole rat: a long-lived mammalian model for biogerontology and biomedical research,” ILAR J 52(1): 41-53.
14. “a kind of cave-dwelling salamander”: The evolutionary biologist John Speakman uses the olm to help further dismantle the oxidative-stress theory of aging, in “The free-radical damage theory: Accumulating evidence against a simple link of oxidative stress to ageing and lifespan,” Bioessays 33: 255–259 (2011).
15. “sequence the naked mole rat genome”: E. B. Kim et al. (2011), “Genome sequencing reveals insights into physiology and longevity of the naked mole rat,” Nature 479(7372): 223-227.
Chapter 13: Fast Forward
1. “simply feeding his lab animals every other day”: Anton J. Carlson and Frederic Hoelzel, “Apparent Prolongation of the Lifespan of Rats by Intermittent Fasting,” Journal of Nutrition, March 1946 31:363-75; the Spanish nursing-home study is described by Johnson et al., (2006), “The effect on health of alternate day calorie restriction: eating less and more than needed on alternate days prolongs life.” Medical Hypotheses 67(2): 209-211. Longo’s take: “The question is, did the 60 that were fed every other day wish they were dead? Probably yes.”
2. “their asthma symptoms also cleared up”: J. B. Johnson et al. (2007), “Alternate day calorie restriction improves clinical findings and reduces markers of oxidative stress and inflammation in overweight adults with moderate asthma,” Free Radical Biology in Medicine 42(5): 665-674.
3. “Studies of Muslims during Ramadan”: For a good review of studies on religious fasting and health, check out John F. Trepanowski et al., “Impact of caloric and dietary restriction regimens on markers of health and longevity in humans and animals: a summary of available findings,” Nutrition Journal 2011, 10:107 (http://www.nutritionj.com/content/10/1/107).
4. “brain-derived neurotrophic factor”: Mark Mattson has amassed a string of fascinating studies on diet and fasting, but the brain work is the most interesting. In this study, he and his team found that intermittent fasting improved glucose handling AND protected neurons, independent of the total number of calories consumed: R. M. Anson et al. (2003), “Intermittent fasting dissociates beneficial effects of dietary restriction on glucose metabolism and neuronal resistance to injury from calorie intake,” Proceedings of the National Academy of Sciences 100(10): 6216-6220.
5. “there’s no one ‘right way’ to do intermittent fasting”: The 8-hour feeding “window” study is at M. Hatori et al. (2012), “Time-restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high-fat diet,” Cell Metabolism 15(6): 848-860. The last couple of years has seen a flood of fasting-based diet books hit the market, from The 8-Hour Diet (loosely based on Panda’s work) to The Every-Other-Day Diet: The Diet That Lets You Eat All You Want (Half the Time) and Keep the Weight Off, by University of Illinois at Chicago professor Krista Varady (New York: Hyperion, 2013). Then there’s the UK bestseller The Fast Diet, by Michael Mosley (New York: Atria Books, 2013), which advocates fasting two days out of seven (and which Longo says has no basis in any research whatsoever). Fasting, in other words, is trendy.
6. “blocking the TOR pathway caused his yeast to live three times longer”: The Longo group’s breakthrough yeast paper is Paola Fabrizio et al., “Regulation of Longevity and Stress Resistance by Sch9 in Yeast,” Science 13 April 2001: Vol. 292 no. 5515 pp. 288-290. Way more interesting than this sounds.
7. “In some patients, the chemo also appeared to be more effective”: Both the mouse and human fasting plus chemotherapy trials are described in F. M. Safdie et al. (2009), “Fasting and cancer treatment in humans: A case series report,” Aging (Albany NY) 1(12): 988-1007. Larger clinical trials are ongoing, with results expected in later 2015.
8. “he took his precious soil fungus with him”: The discovery and development of rapamycin, by Indian-born Canadian scientist Suren Sehgal, is one of the great serendipitous tales in modern biology. The story is well told in “Rapamycin’s Resurrection: A New Way to Target the Cell Cycle,” in Journal of the National Cancer Institute, October 17, 2001.
9. “rapamycin had significantly extended the lifespan of mice”: D. E. Harrison et al. (2009), “Rapamycin fed late in life extends lifespan in genetically heterogeneous mice,” Nature 460(7253): 392-395. The Times buried the story, and inaccurately described rapamycin as an “antibiotic.”
10. “rapamycin actually reversed cardiac aging in elderly mice”: J. M. Flynn et al. (2013), “Late-life rapamycin treatment reverses age-related heart dysfunction,” Aging Cell 12(5): 851-862.
11. “rapamycin would likely extend lifespan in mammals”: M. V. Blagosklonny, (2006), “Aging and immortality: quasi-programmed senescence and its pharmacologic inhibition,” Cell Cycle 5(18): 2087-2102.
12. “it’s more like a program gone wrong”: The term “hyperfunction” was first used by London gerontologist David Gems; see D. Gems, and Y. de la Guardia (2013), “Alternative Perspectives on Aging in Caenorhabditis elegans: Reactive Oxygen Species or Hyperfunction?” Antioxidant Redox Signalling 19(3): 321-329.
13. “Called Laron little people”: J. Guevara-Aguirre et al. (2011), “Growth Hormone Receptor Deficiency Is Associated with a Major Reduction in Pro-Aging Signaling, Cancer, and Diabetes in Humans,” Science Translational Medicine 3(70): 70ra13.
14. “middle-aged people who had eaten a diet high in dairy and meat”: M. E. Levine et al. (2014), “Low protein intake is associated with a major reduction in IGF-1, cancer, and overall mortality in the 65 and younger but not older population,” Cell Metabolism 19(3): 407-417.
Chapter 14: Who Moved My Keys?
1. “significant cognitive decline is already evident”: Archana, Singh-Manoux, Mika Kivimaki, M. Maria Glymour, Alexis Elbaz, Claudine Berr, Klaus P. Ebmeier, Jane E. Ferrie, and Aline Dugravot, “Timing of Onset of
Cognitive Decline: Results from Whitehall II Prospective Cohort Study.” BMJ Vol. 344, 2012. Journal Article. doi:10.1136/bmj.d7622. For the depressing fruit-fly information, thank Hsueh-Cheng Chiang, Lei Wang, Zuolei Xie, Alice Yau, and Yi Zhong. “Pi3 Kinase Signaling Is Involved in Aβ-Induced Memory Loss in Drosophila.” Proceedings of the National Academy of Sciences 107, no. 15 (April 13, 2010 2010): 7060-65.
2. “Her name was Auguste D.,”: The whole fascinating story is retold here, complete with original drawings and photographs. Interestingly, Auguste D. is now thought to have suffered from arteriosclerosis of the brain, not Alzheimer’s. M. B. Graeber, S. Kosel, R. Egensperger, R. B. Banati, U. Muller, K. Bise, P. Hoff, et al., “Rediscovery of the Case Described by Alois Alzheimer in 1911: Historical, Histological and Molecular Genetic Analysis,” Neurogenetics 1, no. 1 (May 1997): 73-80.
3. “In clinical trials in actual patients, they failed to work”: J. L. Cummings, T. Morstorf, and K. Zhong, “Alzheimer’s Disease Drug-Development Pipeline: Few Candidates, Frequent Failures.” [In English]. Alzheimer’s Research and Therapeutics 6, no. 4 (2014): 37. Also “Alzheimer’s Theory That’s Been Drug Graveyard Facing Test,” by Michelle Fay Cortez and Drew Armstrong, Bloomberg News, December 12, 2013.
4. “the better writers’ brains were also less gunked-up”: D. Iacono, W. R. Markesbery, M. Gross, O. Pletnikova, G. Rudow, P. Zandi, and J. C. Troncoso, “The Nun Study: Clinically Silent Ad, Neuronal Hypertrophy, and Linguistic Skills in Early Life.” Neurology 73, no. 9 (Sep 1 2009): 665-73. The Nun Study generated many fascinating publications (available at https://www.healthstudies.umn.edu/nunstudy/publications.jsp), and also a book: David Snowdon, Aging with Grace: What the Nun Study Teaches Us About Leading Longer, Healthier, and More Meaningful Lives (New York: Bantam Books, 2001).