A protein that protects against aging-related diseases maintains telomere length and integrity, Palacios et al. reveal.
Telomeres protect chromosome ends but grow shorter with age, potentially contributing to several age-associated illnesses. Budding yeast telomeres are partly maintained by a deacetylase called Sir2, but whether the mammalian orthologue of this protein, SIRT1, has a similar function is unclear. Mice overexpressing SIRT1 have an increased healthspan—remaining healthy for longer than wild-type littermates. Palacios et al. examined telomeres from these mice, as well as from animals that lack SIRT1 entirely.
SIRT1-deficient mice had shorter telomeres, whereas SIRT1 overexpression boosted telomere length, preventing them from shortening as the mice grew older. This latter effect required the activity of telomerase enzyme, a major contributor to telomere production. Yet SIRT1 may also influence a second maintenance pathway called alternative lengthening of telomeres, or ALT. SIRT1 overexpression increased the amount of homologous recombination at chromosome ends, a key step in the ALT pathway. SIRT1 boosted homologous recombination along the rest of chromosomes as well, suggesting that the deacetylase promotes DNA repair. On the other hand, SIRT1-deficient cells showed increased damage at their chromosome ends.
SIRT1 therefore maintains telomere length and integrity, which may explain why SIRT1-overexpressing mice stay healthier for longer. Telomeres re-grow when differentiated cells are reprogrammed into an embryonic stem cell–like state. Palacios et al. found that SIRT1 binds to the elongated telomeres of these induced pluripotent stem cells. Senior author Maria Blasco now wants to investigate whether SIRT1 contributes to telomere extension during reprogramming.