Sirtuins are involved in the regulation of metabolism in various ways, and are clearly quite important to cell function as their structure is very similar in species as divergent as yeast, flies, and humans. Sirtuin 1 as a target for interventions in aging was intensely overhyped and likely not actually very useful in a practical sense. Sirtuin 3 is more interesting, based on research suggesting that it could have calorie restriction mimetic effects, and is involved in mitochondrial function, well known to have a role in aging. Sirtuin 6 is also interesting, as it slows aging in mice, but the mechanisms involved are less well understood. A company is presently working on gene therapies based on sirtuin 6 upregulation. Here, researchers report on their production of profile of these sirtuins in a small population of people at various ages, which might be of interest in the context of growing efforts to modestly slow aging by targeting sirtuins 3 and 6.
While modulation of SIRT1, SIRT3 and SIRT6 extends lifespan in model organisms, evidence in extreme-age humans is scarce. We quantified protein and mRNA levels, and protein-to-mRNA ratios for SIRT1, SIRT3 and SIRT6 in buccal epithelial cells obtained from healthy young adults, middle/late-aged individuals and nonagenarians/centenarians residing in a longevity-enriched region of south-eastern Azerbaijan. The cohort comprised 23 participants, stratified by sex and cardiovascular disease (CVD) status (5 per sex/CVD subgroup).
Our study has shown that although SIRT1, SIRT3 and SIRT6 levels predictably fell with age, the magnitude of these declines was significantly influenced by both sex and baseline cardiovascular health. Women retained higher absolute pools of SIRT1 and SIRT3 and exhibited a smaller loss of SIRT6 than men; their protein-to-mRNA ratios - our proxy for translational efficiency - rose by ≈30% for SIRT3 and SIRT6, whereas the male increase was modest. This pattern is consistent with hormone-dependent regulation: estrogens acting through estrogen receptor (ER)-α/β up-regulate SIRT1 transcription in endothelial and cardiac cells, via the estradiol-ERα interaction boost SIRT3 expression and mitochondrial targeting, enhancing oxidative phosphorylation, antioxidant defenses, and mitophagy for improved mitochondrial health and enhance SIRT6 activity by shielding critical acetyl-lysine residues, whereas androgens are neutral or even suppressive.
Our findings likewise showed that the presence of cardiovascular disease (CVD) reshapes the sirtuin axis far more dramatically than chronological aging and sex. We observed a decline in SIRT1, SIRT3, and SIRT6 levels, broadly consistent with a ~50% reduction in SIRT1 reported in ischemic heart disease cohorts and a ~35% decline in SIRT3 under pressure-overload conditions. In contrast, SIRT6 behaves differently: although its absolute protein level fell by ~73%, the protein-to-mRNA ratio remained virtually unchanged This pattern exemplifies translational buffering whereby cells upregulate translation of selected proteins to maintain critical functions despite drops in mRNA levels. This is more accurately framed as an emergency protective buffer, rather than a pathological driver.
This pilot study is the first to profile SIRT1, SIRT3 and SIRT6 across sex, age and cardiovascular health, defining a unified "sirtuin phenotype" that integrates nuclear energy sensing, mitochondrial integrity and chromatin maintenance as axes of cellular resilience. Although based on a small, cross-sectional cohort, the large and internally consistent effect sizes pave the way for longitudinal studies to validate sirtuin translational efficiency as a predictive biomarker of healthy ageing and cardiovascular resilience across sexes and as a target for sirtuin-modulating interventions aimed at extending healthspan.
Link: https://doi.org/10.3390/biology14101353
View the full article at FightAging
