Shortcuts for supercentenarians

The aging process is complex and multifaceted, but slowing it may be easier than we thought—and in biogerontology, there might be such a thing as a free lunch.

In the 1930s, biogerontologist Clive McKay found that rats whose diets were reduced to sixty per cent of what they would eat normally were living healthily, with glossy fur and eyes unclouded by cataracts, at ages where their normally-fed compatriots were dying1. McKay thought wrongly that it was stunting development that extended lifespan; Ed Masoro would later find that caloric restriction could be started during adulthood and cause a similarly profound drop in mortality2. Calorie restriction (or CR) has been found to work in mice, rats, worms, fruit flies and yeast, and probably works in higher organisms as well3. A trial at the University of Wisconsin–Madison is attempting to determine the effects of CR in rhesus macaques, the most humanlike animals yet used in such experiments. While the final results of the trial are many years away—these monkeys do live for 25 years on average, after all—already the animals on CR show signs of increased lifespan and ‘youthspan’, with normally-fed monkeys dying at three times the rate of calorie restricted ones4.

Biogerontology’s grand claim—that we can control and slow aging—is thus made credible. If simple interventions can reliably increase lifespan in animals, they almost certainly work in humans, too. The island of Okinawa off the southernmost point of Japan harbours the world’s largest population of supercentenarians (those lucky few who live for a century or longer), and it is likely no coincidence that the Okinawan Japanese have a culture of leaving the stomach part empty at the end of every meal.

Of course, calorie restriction is hardly fun. The regimen has side-effects and few would be able to stomach a one-third reduction in their calorie intake. But as proof-of-principle, CR shows that there are low-hanging fruit in life extension: simple biological switches that can increase longevity. Finding a simple way of flicking those switches is a major goal of modern biogerontology.

As a phenomenon, CR is intriguing: if we have genes that specifically lengthen animal lifespan, as xenometabolic enzymes, heat stock proteins and protein chaperones seem to5, why aren’t those genes switched on all the time? Certainly if living longer was evolutionarily favourable, they would be. But the opportunity cost of expending energy on cellular maintenance is investing less in reproduction. In species where early and prolific reproduction is evolutionarily favored, faster aging is promoted at the expense of extended lifespans and long reproductive careers. The battery of life-extending genes that lie dormant within so many species are only activated in times when food is scarce and conditions harsh, delaying reproduction to concentrate on surviving the drought before returning to full reproductive capacity. Simply, CR probably switches on a form of reproductive diapause—a way of adjusting the balance between reproduction and longevity.

Sirtuins are a major candidate in the search for ‘CR mimetics’, or drugs that trick the body into thinking calories are few and far between, so simulating CR. Notable among them is resveratrol, a compound found in grape skins and present in red wine, which stirred much enthusiasm in the field (and not a few high-profile headlines). If these chemicals could trick our bodies into thinking their calorie intake was being drastically reduced—if they could switch on longevity genes—we could enjoy longer lifespans and healthspans. With most people having few children late in life, the cost of reduced fertility would not be a hard one to bear.

David Sinclair was formerly a postdoctoral researcher working for Leonard Guarente in MIT where he discovered that the protein Sir2 prevents the formation of ERCs (extrachromosomal rDNA circles, a key biomarker of aging in yeast). Another postdoc in that lab, Matthew Kaeberlein, found that overexpressing the Sir2 gene extended yeast lifespan. The gold rush for CR mimetics began, with Sinclair founding Sirtris, a company trying to develop and commercialise sirtuin-based anti-aging compounds6. His firm was later acquired by pharmaceutical giant GlaxoSmithKline for a staggering $720million, symbolic of the commercial significance a drug that could slow aging would have.

But the effectiveness and pututative mechanism of resveratrol has been called into question. It extends the lifespan of mice, but only those fed a high-fat diet. Later work by Kaeberlein failed to find any life-extending effect of resveratrol on several strains of yeast7. The compound was found to increase the lifespan of the humble nematode C. elegans, but its activity may be unique to that species alone (a ‘private’ rather than ‘public’ mechanism of aging). More worryingly, a 2010 study by David Gems and Linda Partridge at UCL’s Institute for Healthy Ageing found that sirtuin overexpression left fly lifespans unchanged and caused only minimal life extension in worms, casting doubt over the entire premise that firms like Sirtris are counting on8.

Gems recently made newspaper headlines when his laboratory published a paper claiming poor-quality research was to blame for the conflicting results9. Specifically, poorly-controlled genetics (such as sirtuin overexpressing animals picking up other life-extending mutations) seem to account for the life-extending properties described by previous researchers, and Gems showed this by demonstrating that sirtuin overexpression and lifespan extension were separable genetically. Guarente challenges this in the same issue of Nature, claiming that he used the best techniques available at the time, and that carefully-controlled followup work confirms a (somewhat smaller) life-extending effect10.

It might be years before sirtuins’ mysteries are properly described. Some think that these compounds don’t activate the sirtuin pathway at all, perhaps acting via TOR (target of rapamycin) signalling. Other sirtuin activators with potencies orders of magnitude greater than resveratrol are under development and may work where resveratrol failed. But even if Sirtris fails to be the jewel in GlaxoSmithKline’s crown and sirtuins act by entirely different pathways, CR mimetics might be a quick and dirty way to extend lifespan without needing to know much at all about the underlying processes of aging.

First posted in Nature Student Voices.

  1. McCay CM, Crowell MF, Maynard LA. The effect of retarded growth upon the length of life span and upon the ultimate body size. J Nutr. 1935;10:63–79. 

  2. Masoro EJ. Caloric restriction-induced life extension of rats and mice: A critique of proposed mechanisms, Biochimica et Biophysica Acta 2009, 10:1040–1048. doi:10.1016/j.bbagen.2009.02.011. PMID: 19250959 

  3. McDonald RB, Ramsey JJ. Honoring Clive McCay and 75 Years of Calorie Restriction. J Nutr. 2010;7:1205–1210. PMID: 20484554

  4. Colman RJ et al. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 2009 Jul 10;325(5937):201-4. PMID: 19590001 

  5. Gems D, McElwee JJ. Broad spectrum detoxification: the major longevity assurance process regulated by insulin/IGF-1 signaling? Mech Ageing Dev. 2005 Mar;126(3):381-7. PMID: 15664624 

  6. Garber, K. A mid-life crisis for aging theory. Nature Biotechnology 26, 371 - 374 (2008) doi:10.1038/nbt0408-371 

  7. Kaeberlein M et al. Substrate-specific activation of sirtuins by resveratrol. J Biol Chem. 2005 Apr 29;280(17):17038-45. PMID: 15684413 

  8. Bass TM, Weinkove D, Houthoofd K, Gems D, Partridge L. Effects of resveratrol on lifespan in Drosophila melanogaster and Caenorhabditis elegans. Mech Ageing Dev. 2007 Oct;128(10):546-52. PMID: 17875315 

  9. Burnett, C et al. Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila. Nature 2011 Sep 21;477(7365):482-5. doi: 10.1038/nature10296. PMID: 21938067 

  10. Viswanathan M and Guarente L. Regulation of Caenorhabditis elegans lifespan by sir-2.1 transgenes. Nature 2011 Sep 21;477, E1–E2. doi: 10.1038/nature10440.