umerous studies have shown that a diet of reduced calories, also known as caloric restriction (or CR) promotes lifespan extension by up to 50% in a wide range of organisms, including yeast, worms, flies and mice. (1) However there are some exceptions, including wild mice and houseflies. (2,3) In mammals CR triggers physiological changes that improve glucose control; in rodents and humans CR decreases insulin and glucose levels and improves insulin sensitivity. These metabolic changes are relevant to aging because decreasing insulin signaling is implicated in the longevity of most organisms. (4) It has long been known that if you want to study premature aging study diabetics.
Does CR lengthen life... or just make it seem interminably longer?
Traditionally, the benefits of CR have been attributed to a class of genes known as sirtuins. Activation of sirtuins, either by restricting calories or by pharmacological means, extends the lifespan and/or promotes the health of a wide variety of organisms from yeast to mammals. The most-studied sirtuin is SIRT1, and multiple studies provide support for the strong role for SIRT1 in the beneficial effects of CR. Rodent studies show that CR upregulates SIRT1 expression in a variety of tissues, such as brain, kidney, liver, white adipose, and skeletal muscle (5). Nonetheless, SIRT1 induction is not observed in all CR studies, and it may be induced in a tissue-specific manner or even decreased. (6)
The discovery that sirtuins can also be modulated directly by small molecules has opened up the possibility of mimicking the benefits of CR without having to restrict calories. SIRT1-activating compounds (STACs) include resveratrol, quercetin, fisetin (3,7,3’,4′-tetrahydroxyflavone), butein (3,4,2”,4′-tetrahydroxychalone) and analogs of the B vitamin nicotinamide. These molecules have been shown to extend life span in a wide variety of organisms from yeast to flies to obese mice, (7–11) however, some labs report little or no life span extension. (12,13)
Wheeling into Longevity City
A just-published study from the journal Functional Ecology may shed new light on the mechanisms of caloric restriction and point to potential benefits yet unanticipated. (14) Shugo Watabe at the University of Tokyo experimented with rotifers, microscopic or near-microscopic creatures known as “Wheel Animals’ and typically found in fresh water. Like many other studies Watabe found that CR increased their lifespan. However what was especially interesting is that fact that Watabe also observed that the offspring of the rotifers in question also lived longer than normal. In other words, caloric restriction of the parent produced inheritable changes in the metabolism of the offspring.
New research may help keep Rotifers out of old age homes.
Rotifers are virtually all-female and reproduce by a process known as parthenogenesis, the result being (give or take the odd mutation) that a rotifer’s daughters are genetically identical to her. This makes rotifers convenient subjects for studies of epigenetic inheritance. Professor Watabe looked at the expression levels of two antioxidant enzymes, catalase and manganese superoxide dismutase (Mn SOD) in the rotifer Brachionus plicatilis during two consecutive generations.
Without CR the animals lived for an average of 8.8 days. With it they lived for 13.5 days. However, things got interesting when Watabe did the same thing with the rotifers’ offspring. The daughters of those rotifers which had been fed as much as they could eat lived for 9.5 days if treated likewise and 14.4 if put on CR. However, those born of calorie-restricted mothers lived for 12.7 and 16.8 days respectively. Something in the calorie restricted mother had programmed a function in the daughter that allowed it to live longer even if it was fed as many calories as it desired.
It appears that the daughters from the CR-treated mothers were endowed at birth with a higher ability to resist oxidative stress due to increased levels of the enzyme catalase in their messenger RNA (mRNA). This was not observed for manganese SOD, the other anti-oxidant studied.
Biochemists love catalase because it is darn near close to a ‘perfect enzyme’. All known animals use catalase in every organ, with particularly high concentrations occurring in the liver. Its major job is to break up hydrogen peroxide (H2O2) into water and oxygen. Hydrogen peroxide is a harmful by-product of many normal metabolic processes, and has been implicated in the causation of many problems, from grey hair and the skin condition vitiligo. So to prevent damage, it must be quickly converted into other, less dangerous substances. Catalase has the amazing dual-function ability to take hydrogen peroxide and any number of toxins, smash them together and inactivate them both.
Finally, catalase is a textbook example of enzyme efficiency: It is claimed that catalase is at the upper limit of what is known as a diffusion-controlled limit –basically the frequency of how often enzymes and their substrates bang into each other. In short, it is amazingly efficient at what it does. One molecule of catalase can convert millions of molecules of hydrogen peroxide to water and oxygen per second.
Potential and Pratfalls
If inherited epigenetic changes were causing daughter rotifers to produce more catalase, it would raise the question of whether a similar thing happens in other species and, if so, whether it might be induced therapeutically, without all the tedious business of a lifetime’s starvation. That would certainly be worth looking at. According to a report by the Rand Corporation, such a drug would be among the most cost-effective breakthroughs possible in medicine, providing Americans more healthy years at less expense (an estimated $8,800 a year) than new cancer vaccines or stroke treatments. (15)
One possible complication comes to mind which, if nothing else, demonstrates the complexity of the problem. If caloric restriction yields such metabolically efficient offspring why did the children of caloric-deprived mothers during the Dutch ‘Hongerwinter‘ wind up instead with diabetes and obesity? One could always argue that there is a distinct difference between caloric restriction using nutrient-dense foods and starvation, and that may indeed be true. Only time will tell.
An area of considerable debate is the role of sirtuins in tumor causation and cancer cell proliferation, for which there is a large and often contradictory literature. One of the confusing aspects of SIRT1 is that it plays a dual role in cell survival and cell death and can be modulated in different directions by a variety of different stimuli. Although CR is arguably the most effective way to prevent cancer in rodents and primates, which some view as an indication that sirtuins are tumor suppressors, some sirtuins, such as SIRT1, have prosurvival functions, which could be a sign that they promote tumorigenesis. (16)
Sirtuins like SIRT1 bind to and deacetylate a number of important gene regulaotry factors—such as the PPARs and FOXO family of transcription factors —which themselves drive metabolic responses such as insulin secretion, gluconeogenesis, and fatty acid oxidation. Histone deacetylation is a hallmark of epigenetic control of gene expression, and probably implies that there are multiple epigenetic effects that result from CR.
Post-genomic, transgenerational epigenetic inheritance certainly does a much better job of explaining the tendencies for longevity to run in certain families than the traditional genetic determinism theories.
- Sinclair DA. Toward a unified theory of caloric restriction and longevity regulation. Mech. Ageing Dev. 2005;126:987–1002
- Harper JM, Leathers CW, Austad SN. Does caloric restriction extend life in wild mice? Aging Cell. 2006;5:441–449.
- Cooper TM, Mockett RJ, Sohal BH, Sohal RS, Orr WC. Effect of caloric restriction on life span of the housefly, Musca domestica. FASEB J. 2004;18:1591–1593.
- Guarente L, Kenyon C. Genetic pathways that regulate ageing in model organisms. Nature. 2000;408:255–262.
Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, et al. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science. 2004;305:390–392.
- Chen D, Bruno J, Easlon E, Lin SJ, Cheng HL, et al. Tissue-specific regulation of SIRT1 by calorie restriction. Genes Dev. 2008;22:1753–1757.
- Yuan Z, Seto E. A functional link between SIRT1 deacetylase and NBS1 in DNA damage response. Cell Cycle. 2007;6:2869–2871.
- Lavu S, Boss O, Elliott PJ, Lambert PD. Sirtuins—novel therapeutic targets to treat age-associated diseases. Nat. Rev. Drug Discov. 2008;7:841–853.
- Bauer JH, Goupil S, Garber GB, Helfand SL. An accelerated assay for the identification of lifespan-extending interventions in Drosophila melanogaster. Proc. Natl. Acad. Sci. USA. 2004;101:12980–12985.
- Wood JG, Rogina B, Lavu S, Howitz K, Helfand SL, et al. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature. 2004;430:686–689.
- Jarolim S, Millen J, Heeren G, Laun P, Goldfarb DS, Breitenbach M. A novel assay for replicative lifespan in Saccharomyces cerevisiae. FEMS Yeast Res. 2004;5:169–177.
- Viswanathan M, Kim SK, Berdichevsky A, Guarente L. A role for SIR-2.1 regulation of ER stress response genes in determining C. elegans life span. Dev. Cell. 2005;9:605–615.
- 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;128:546–552.
- Kaneko, G., Yoshinaga, T., Yanagawa, Y., Ozaki, Y., Tsukamoto, K. and Watabe, S. , Calorie restriction-induced maternal longevity is transmitted to their daughters in a rotifer. Functional Ecology, no. doi: 10.1111/j.1365-2435.2010.01773.x
- One for the Ages: A Prescription That May Extend Life (www.nytimes.com/2006/10/31)
- D’Adamo PJ. ‘Sirtuins’ in: Fundamentals of Generative Medicine, Volume I (2010) Drum Hill Books, Wilton CT USA