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Two recent papers describe a relationship between the lifespan regulator Sirt1 (ortholog of the yeast Sir2p, member of the creatively named “sirtuin” family of proteins) and cellular senescence: As cells lose their ability to divide, they downregulate Sirt1. From Sasaki et al.:

… Mouse SIRT1 decreased rapidly in prematurely senescent (p44 Tg) MEFs, remained high in MEFs with delayed senescence (Igf-1r-/-), and was inversely correlated with senescence-activated beta-galactosidase (SA-betaGal) activity. Reacquisition of mitotic capability following spontaneous immortalization of serially passaged wild-type MEFs restored the level of SIRT1 to that of early passage, highly proliferative MEFs. In mouse and human fibroblasts, we found a significant positive correlation between the levels of SIRT1 and proliferating cell nuclear antigen (PCNA), a DNA processing factor expressed during S-phase. … Finally, loss of SIRT1 with age was accelerated in mice with accelerated aging but was not observed in long-lived growth hormone-receptor knockout mice. Thus, as mitotic activity ceases in mouse and human cells in the normal environment of the animal or in the culture dish, there is a concomitant decline in the level of SIRT1.

The p44 protein mentioned in the abstract is a short isoform of p53. Two years ago, the same lab (Heidi Scrable’s group) demonstrated that p44 overexpression results in hyperactivation of the IGF-1 signaling pathway, resulting in earlier cellular senescence and a shortened lifespan. Hence, the paper’s paradigm for both accelerating and delaying senescence (or, in the in vivo work, lengthening and shortening the lifespan of the organisms) involves manipulation of the IGF axis.

These results are consistent with and complementary to those of Sommer et al., who used a hyperactive allele of keratinocyte differentiation factor (and p53 target) p63 to stimulate premature aging in the skin. They also observed decreases in SIRT1 levels:

p63 is highly expressed in the skin and appears to be an early marker of keratinocyte differentiation. To examine the role of p63 in vivo, we generated transgenic mice that overexpress DeltaNp63alpha in the skin. These mice exhibited an accelerated aging phenotype in the skin characterized by striking wound healing defects, decreased skin thickness, decreased subcutaneous fat tissue, hair loss, and decreased cell proliferation. The accelerated skin aging was accompanied by a dramatic decrease in longevity of the mice. We found that aging in DeltaNp63alpha transgenic mice and other mouse models correlated with levels of Sirt1, a mammalian SIR2 orthologue thought to extend the lifespan in lower species. Moreover, increased DeltaNp63alpha expression induced cellular senescence that was rescued by Sirt1. Our data suggest that DeltaNp63alpha levels may affect aging in mammals, at least in part, through regulation of Sirt1.

In essence, both of these papers describe a protein whose expression pattern correlates positively with proliferative capacity and negatively with cellular senescence. Were it not for the fact that Sirt1 and homologs pop up in every lifespan regulation story we’d ever heard, we wouldn’t be getting all excited —” but they do, and so we are.

The papers also suggest a connection between “lifespan” as it is considered in two different senses, proliferative/replicative lifespan (of a cell line) and organismal lifespan (of a body) —” that are not necessarily synonymous, despite their interchangeability in some contexts (yeast) and the propensity of some scholars in the field to treat replicative senescence as though there were an evidence-based consensus that it is an explicit model for organismal aging per se.

We knew already that Sirt1 positively regulates (organismal) lifespan in the smaller metazoans (worms and flies); here we see that Sirt1 expression is itself negatively regulated over the (proliferative) lifespan of the larger ones (mouse and human). It is not yet clear whether or in which direction this Sirt1 downregulation affects proliferative lifespan. In these two papers, senescence brings a decrease in Sirt1 levels; put another way, cells with greater replicative capacity have higher Sirt1 levels. It has been reported elsewhere, however, that Sirt1 expression limits proliferative lifespan: removal of the single functional SIRT1 allele from a heterozygous MEF line dramatically delays senescence. Put another way, cells with lower Sirt1 levels have a greater replicative capacity. So it’s not going to be simple.

Sorting through that puzzle is beyond the scope of these two papers, which have done a good job of establishing the initial finding. I’m sure both labs are busily working out the next step.