Debates over the role of sirtuin proteins in ageing are maturing into functional assessments of the individual proteins. It seems that overexpression of a specific sirtuin can extend lifespan in male mice. See Letter p.218
Abraham Lincoln once said that God must have loved the common people because he made so many of them. Nature must feel the same way about the sirtuins, a large family of proteins that achieved celebrity status when one member was found to increase lifespan in yeast1. But are the mammalian sirtuins the rock stars of an ensemble of anti-ageing proteins, or merely members of the entourage? The original model, proposed in about 2005, that sirtuins have broadly evolutionarily conserved roles in promoting longevity per se is now being refined through more detailed functional investigations of each sirtuin2. On page 218 of this issue, Kanfi et al.3 follow this trend by reporting that overexpression of a sirtuin called SIRT6 leads to a modest extension of lifespan in male, but not female, mice*.
Does an extension of lifespan imply an effect on ageing? Not necessarily: interventions unrelated to ageing, such as giving insulin to a person with type I diabetes, can increase mean and maximal lifespan. The lifespan extension observed by Kanfi and colleagues in SIRT6-overexpressing male mice could be explained, at least partially, by SIRT6 acting as a tumour suppressor. Because male mice have a higher incidence of spontaneous cancer than female mice (incidences of 81% and 50%, respectively, were observed in this study), an anticancer protein (perhaps SIRT6?) would have a larger effect on lifespan in males than in females.
Proving that a lifespan-increasing intervention indeed acts by delaying ageing processes is not a simple matter. For example, acceptance of the idea that lifespan extension by caloric restriction (a diet with reduced calorie intake) reflects a genuine deceleration of ageing emerged gradually from evidence4 that restriction slows age-related changes in the properties of proliferative and non-proliferative cells in many tissues, and does so in multiple organ systems. Similar cases are being constructed by researchers proposing that dwarf mice could act as models for slowed ageing5.
Reports of lifespan increases in mutant or drug-treated mice, particularly studies in which the observed effects are modest, often prove difficult for other laboratories to repeat. This is presumably due to subtle but crucial variations in the animals' diet or genetic background, or in husbandry practices6. Moreover, the preference for publication of positive over negative findings inevitably inserts a smattering of false positive results into the literature, and these can be identified only by attempts to replicate experiments. One strength of Kanfi and colleagues' paper3 is that SIRT6 overexpression increased male lifespan in each of two groups of mice, which were derived from two different founder animals. However, the test for maximal lifespan — usually taken as stronger evidence than an effect on median longevity alone — reached statistical significance in only one of the two mouse groups. If the longevity effect seen by the authors proves robust, determining whether SIRT6 overexpression does indeed slow ageing will still require follow-up studies analysing a wide range of age-sensitive endpoints.
In their article, Kanfi and colleagues include some observations hinting at potential mechanisms by which SIRT6 overexpression might affect the lifespan of male mice. Compared with their normal counterparts, SIRT6-overexpressing males had modestly reduced serum levels of the hormone IGF-1, and the signalling activity of IGF-1 receptors was weaker in peri-gonadal fat tissue in males but not in females. Previous reports have found that SIRT6 attenuates intracellular signalling initiated by IGF-1 and insulin7. Furthermore, dramatic deficits in IGF-1 and/or growth hormone (GH, which stimulates IGF-1 secretion) lead to slower ageing and increased lifespan in at least four varieties of mutant mouse6. And mutations in the gene encoding the GH receptor in humans are associated with strong protection against diabetes and cancer8. So, it is plausible that SIRT6 overexpression in mice might work through blunting of the GH/IGF-1 pathway. Evidence9 that rat longevity can be augmented by surgical removal of intra-abdominal — but not subcutaneous — fat has begun to focus attention on metabolic and hormonal effects on specific fat depots as potential levers for pharmacological control of ageing.
It is noteworthy that the effects of SIRT6 overexpression reported by Kanfi et al.3 are seen only in male mice. Previous results6, by contrast, indicate that mutations in components of the GH/IGF-1 pathway usually have greater effects on longevity in female mice. This apparent discrepancy might be explained by differences between the mice in terms of underlying disease proclivities, levels of sex-specific hormones, inter-animal conflict or fat-tissue biology, leading to gender-specific responses to mutations, drugs and nutritional interventions. Working out the basis for these sex-specific interactions should provide clues to the mechanisms involved in these anti-ageing manipulations, and perhaps even help to answer the vexing question of why women tend to live longer than men.
SIRT6 has other roles that could foster longer lifespan (Fig. 1). It promotes chromosomal stability by several mechanisms, and above-normal SIRT6 expression increases the efficiency of DNA repair10. SIRT6 also reduces the expression of genes regulated by the NF-κB and HIF-1α proteins, which have roles in inflammation, cancer and, potentially, longevity11,12. It will be of interest to assess these aspects of SIRT6's function in mice overexpressing the protein, and to test more definitively whether they contribute to protection against cancer and promotion of longevity.
The recent spate of activity in sirtuin research, now supplemented by the present work, supports the case for placing the sirtuins on the front line of ageing research, sitting cheek by jowl with other promising contestants, such as the proteins TOR, FoxO, AMPK, NRF2 and ATF4. To paraphrase Winston Churchill, the discoveries of Kanfi et al. do not by any means represent the end of sirtuin research, nor even the beginning of the end. But they are, perhaps, the end of the beginning.
*This article and the paper3 under discussion were published online on 22 February 2012.