Sirtuin 2 Overexpression Fails to Extend Life in Mice
One long-lasting result of the hype engineered over sirtuin 1 overexpression as a possible avenue to modestly slow aging is a continued focus on other sirtuins in the context of aging. Sirtuin 1 overexpression turned out to be entirely unimpressive, a dead end. Sirtuin 6, however, is more interesting, and overexpression in mice does modestly extend life span, possibly by improving DNA repair efficiency. It may also be the case that sirtuin 3 overexpression can improve mitochondrial function to a great enough degree to also be interesting.
On the whole, however, this sort of approach to manipulating metabolism has yet to produce gains in mouse life span that come close to that achieved by calorie restriction. And gains in mouse life span dwindle when the same strategies are applied to longer-lived species, in which evolution has already implemented many of the gains that can be achieved in short-lived species. Still, the research community continues down this road, and sirtuins remain on the agenda. That leads to studies such as the one reported in today's open access paper, in which researchers rule out sirtuin 2 upregulation as an area of interest.
SIRT2 transgenic over-expression does not impact lifespan in mice
The sirtuin NAD+-dependent deacylase family of enzymes contains seven members, playing diverse roles in epigenetic regulation, DNA repair, and metabolic homeostasis. Interest in these proteins was sparked by initial findings on the role of Sir2 in yeast replicative lifespan, and subsequent interest in the mammalian homologue SIRT1. This was further compounded by the identification of small molecule allosteric activators for SIRT1, with these compounds demonstrating potential in preclinical models of disease. Whole-body transgenic over-expression of SIRT1 impacts some aspects of late-life health, it does not increase overall lifespan in mice, unlike the transgenic over-expression of another nuclear sirtuin, SIRT6. This may be complicated by tissue specific effects, as unlike whole-body overexpression, tissue specific SIRT1 overexpression in the hypothalamus results in increased overall lifespan. It is currently unknown whether altered activity of other members of this family can impact mammalian ageing.
One member of this family, sirtuin-2 (SIRT2) was previously found to regulate stability of BubR1, which has been implicated in maintaining accurate chromosome segregation during mitosis to prevent cellular senescence during ageing. Transgenic over-expression of BubR1 extends lifespan, while its under-expression results in the accelerated onset of age-related pathologies and shortened overall lifespan. Previously, we showed that SIRT2 transgenic over-expression (SIRT2-Tg) in the context of BubR1 under-expression partially rescued the lifespan of male, but not female mice. Further, we showed that this same SIRT2-Tg allele on a non-progeroid wild-type (WT) C57BL6 background could delay reproductive ageing in mice, with an extended period of functional fertility.
While members of the sirtuin family have been classically studied as NAD+-dependent deacetylase enzymes, SIRT2 is also capable of removing other acyl modifications on lysine residues, including lactylation, crotonylation, myristoylation, and benzoylation. Well-studied substrates for SIRT2 include tubulin, histones, glucose-6phospohate dehydrogenase (G6PD), Foxo1, Foxo3a, p65, IDH1, APCCDH1 and others. SIRT2 has been proposed as a therapeutic target in neurodegenerative disease, though a number of these findings are contradictory. For example, SIRT2 inhibitors can provide neuroprotection against models of Huntington's disease, Alzheimer's disease, and Parkinson's disease; however, SIRT2 deletion impairs axonal energy metabolism, resulting in locomotor disability, with SIRT2 also playing a putative role in reducing neuroinflammation. Similarly, there is evidence for SIRT2 as both a suppressor and promoter of tumour growth, though these roles are likely to be context dependent.
Given this previous work, the aim of this investigation was to establish whether SIRT2 could impact overall lifespan on a non-progeroid background in mice. Here, we characterized aspects of metabolism, development, motor coordination, mitochondrial function, bone health, fertility and overall lifespan in a previously described mouse strain over-expressing SIRT2. While SIRT2 over-expression had impacts on levels of certain metabolites in the brain, we found no impact of SIRT2 overexpression any aspect of overall health or lifespan, suggesting that levels of this protein are not relevant to functional biological ageing and lifespan under standard, non-progeroid conditions.