Longevity mutation suppresses genome instability

Earlier this week we learned that mutations in the kinase SCH9, combined with intervention in the RAS and TOR pathways, can extend the chronological lifespan of yeast by as much as tenfold.

Another paper from the same lab has also shown that mutation in SCH9 can suppress the genomic instability that accompanies loss of function in SGS1. Recall that SGS1 is the yeast homolog of the RecQ-like helicase WRN, which is mutated in the human progeria Werner’s syndrome. From Madia et al.:

Longevity mutation in SCH9 prevents recombination errors and premature genomic instability in a Werner/Bloom model system

Werner and Bloom syndromes are human diseases characterized by premature age-related defects including elevated cancer incidence. Using a novel Saccharomyces cerevisiae model system for aging and cancer, we show that cells lacking the RecQ helicase SGS1 (WRN and BLM homologue) undergo premature age-related changes, including reduced life span under stress and calorie restriction (CR), G1 arrest defects, dedifferentiation, elevated recombination errors, and age-dependent increase in DNA mutations. Lack of SGS1 results in a 110-fold increase in gross chromosomal rearrangement frequency during aging of nondividing cells compared with that generated during the initial population expansion. This underscores the central role of aging in genomic instability. The deletion of SCH9 (homologous to AKT and S6K), but not CR, protects against the age-dependent defects in sgs1-delta by inhibiting error-prone recombination and preventing DNA damage and dedifferentiation. The conserved function of Akt/S6k homologues in lifespan regulation raises the possibility that modulation of the IGF-I–Akt–56K pathway can protect against premature aging syndromes in mammals.

Mutation of SCH9, which extends lifespan on its own, suppresses the longevity-shortening phenotype of SGS1 deletion. Since calorie restriction (CR) has no effect on chromosomal rearrangements in the SGS1 mutants, this study has parsed the contributions of SCH9 and CR to at least one molecular correlate of aging (specifically, genome stability).

The authors argue that their results further demonstrate the importance of genome stability to the aging process, a point on which certain researchers focusing on mammalian aging would agree. The question remains, however: Does genomic instability shorten lifespan by increasing transcriptional noise, as suggested by the Vijg lab’s stochasticity experiments, or via another mechanism?



  1. If genomic instability influences the rate of aging in cells, why is it that cells treated with telomerase have greatly increased replicative lifespans? I would expect the usual rate of genomic damage should make those cells die at their usual pace, unless the increased telomere length enhances stability, and if that is the case, then an intervention that renews (but does not over-lengthen) telomeres should stabilize the genome.

  2. Thanks for your comment, Gary.

    Two answers:

    1) The Longo lab is studying chronological lifespan, as opposed to replicative lifespan; these tend to be regulated differently in yeast (which, by the way, is a free-living single-celled organism and as such is telomerase-positive throughout its lifespan).

    2) Telomerase-expressing cultured mammalian cells do indeed have lengthened replicative lifespans, but these lifespans are shortened if the cells bear mutations that confer genomic instability. Taken together, these data imply that genome stability is not rate-limiting for replicative lifespan, but that it can become rate-limiting if it’s artificially decreased.

    The story is even more complex than that — telomere shortening is interpreted as DNA damage, and critically short telomeres result in chromosomal rearrangements — so genomic stability and telomere length aren’t strictly independent of one another.

Comments are closed.