Sir2 proteins slow ageing in yeast by locking chromatin — the DNA and proteins in chromosomes — into a stable, silent state. Inactivating a Sir2 family protein in mice causes premature ageing and genome instability.
Genomes are exquisitely adapted to provide the information, at the right time and place, for cells to function. Loss of genome integrity has long been implicated in ageing: cancer, for example, occurs more frequently with age and can be caused by genome alterations. Writing in Cell, Mostoslavsky et al.1 now show that, in mice, inactivation of SIRT6 — a protein related to Sir2, which increases lifespan in yeast and worms when overexpressed — causes genome instability and premature ageing.
Ever since the discovery in the late 1940s that low, daily doses of radiation accelerated the signs of ageing in rodents2, loss of genome integrity has been proposed as a universal cause of ageing3. Under normal conditions, the most likely culprits for causing genome deterioration are the reactive oxygen species continually produced during metabolism. It comes as no surprise that the enzymatic systems that detect and repair DNA damage are widely considered candidate longevity mechanisms. Heritable defects in such genome maintenance processes are generally associated with premature ageing syndromes. Werner's syndrome, for example, is caused by lack of the WRN protein that is crucial for some forms of DNA repair and for maintaining the structural integrity of chromosome ends. In both humans and mice, WRN mutations and other defects in pathways that protect genome integrity cause premature ageing4.
Intriguing players in genome maintenance are the silent information regulator (SIR) proteins, which repress gene expression and genome instability in yeast by stabilizing chromatin. The founding member of this family, Sir2, promotes longevity in yeast by protecting regions in the genome that consist of repeated DNA sequences, which are inherently unstable. Moreover, extra copies of Sir2 increase the lifespan of fruitflies and nematodes5. Interestingly, in some species Sir2 has been connected to the 'pro-longevity' effect of both caloric restriction (that is, food deprivation without malnutrition) and the reduced insulin/insulin-like growth factor-1 (IGF-1) signalling that is a response to nutritional stress but can also occur as a consequence of mutations in genes acting in the insulin/IGF-1 cascade5.
The actions of Sir2 are not straightforward and there has been no direct evidence to link Sir2 with ageing in mammals. Its closest mammalian relative, SIRT1, regulates the tumour-suppressor protein p53 and FOXO3 (a gene regulatory factor that is negatively regulated by insulin/IGF-1 signalling) to suppress programmed cell death (apoptosis) and promote cell survival6. Inactivating SIRT1 in mice is mostly lethal, with the few live births dying within weeks from abnormalities that do not resemble ageing7.
Mostoslavsky et al.1 show that inactivation in mice of another Sir2 relative, SIRT6, quickly causes abnormalities that resemble some aspects of ageing, such as thinning of the skin due to loss of subcutaneous fat, and signs of osteoporosis. Cells from these mice showed impaired proliferation and increased genomic instability, possibly because of a defect in base excision repair (BER). This would be the first demonstration that accelerated ageing is associated with a defect in this DNA-repair pathway. BER is especially crucial for removing DNA damage caused by reactive oxygen species. It is unclear how SIRT6 promotes BER, but because Mostoslavsky et al. find that the protein is associated with chromatin, it may regulate accessibility of BER enzymes to the damaged site.
Premature ageing symptoms in mice with defects in DNA repair have been linked to cellular responses to the increased DNA damage, such as apoptosis and cellular senescence (the irreversible cessation of cell division)4. Mostoslavsky et al. found a dramatic increase in apoptosis of lymphocytes — cells active in the immune response — in SIRT6-deficient mice. This was the most likely cause of the severe lymphocyte depletion seen in the animals. Unexpectedly, however, bone marrow transplantation experiments indicated that the lymphocyte depletion was not cell-intrinsic but rather a response to a systemic defect. Analysis of the blood serum of SIRT6-deficient mice revealed extremely low levels of IGF-1, as compared with normal, control animals. IGF-1 strongly inhibits apoptosis in lymphocytes, and the age-related reduction in lymphocyte production by the thymus has been ascribed to a decline in IGF-1 levels with age8. This finding presents us with a paradox, because reduction of IGF-1 signalling is linked with a longer, not a shorter lifespan. How can these results be reconciled?
Life extension conferred by dampening IGF-1 signalling is likely to represent a metabolic switch in the use of resources, away from growth and reproduction with the inevitable side effect of DNA damage, towards increased maintenance and repair5. Although defects in insulin signalling in mammals cause diabetes, reduced IGF-1 signalling extends life in mice9. The attenuation of IGF-1 signalling in the SIRT6-deficient mice may indicate that this switch has been activated as a means to limit the onslaught of spontaneous DNA damage and to upregulate the apoptosis of severely damaged cells. Indeed, modulating IGF-1 signalling, possibly through members of the Sir2 family, may be a general mechanism for coping with environmental stress, including nutrient limitation and genotoxic stress. Interestingly, XpdTTD mutant mice, which harbour a defect in another form of DNA repair known as nucleotide excision repair, display characteristics of accelerated ageing and caloric restriction, suggesting that metabolism adjustment might be a general mechanism to deal with genotoxic stress (Fig. 1)10.
So does SIRT6 connect BER to the IGF-1 signalling pathway? As yet, this is far from clear. For example, neither the nature of the SIRT6 enzymatic activity, nor its potential substrates, is known. Indeed, Mostoslavsky and colleagues' results only indirectly implicate SIRT6 in BER, so although it is reasonable to assume that SIRT6 promotes the access of repair enzymes through chromatin remodelling, there is no direct evidence for this. Also, it is not apparent if and how SIRT6 is involved in regulating the IGF-1 response. Finally, not all degenerative symptoms associated with reduced lifespan necessarily involve the causes that underlie natural ageing. Indeed, the degenerative symptoms observed in SIRT6-deficient mice are far from comprehensive and may well result from developmental defects.
Nonetheless, Mostoslavsky et al.1 provide a potential link in the chain connecting genome instability, metabolic effects and ageing. Ultimately, this may lead to ways of exploiting the role of Sir2 family members in genome maintenance to silence senescence.
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