Aging leads to a gradual decline in physical activity and disrupted energy homeostasis. The NAD⁺-dependent SIRT6 deacylase regulates aging and metabolism through mechanisms that largely remain unknown. Here, we show that SIRT6 overexpression leads to a reduction in frailty and lifespan extension in both male and female B6 mice. A combination of physiological assays, in vivo multi-omics analyses and ¹³C lactate tracing identified an age-dependent decline in glucose homeostasis and hepatic glucose output in wild type mice. In contrast, aged SIRT6-transgenic mice preserve hepatic glucose output and glucose homeostasis through an improvement in the utilization of two major gluconeogenic precursors, lactate and glycerol. To mediate these changes, mechanistically, SIRT6 increases hepatic gluconeogenic gene expression, de novo NAD⁺ synthesis, and systemically enhances glycerol release from adipose tissue. These findings show that SIRT6 optimizes energy homeostasis in old age to delay frailty and preserve healthy aging.

Telomere dynamics have been found to be better predictors of survival and mortality than chronological age. Telomeres, the caps that protect the end of linear chromosomes, are known to shorten with age, inducing cell senescence and aging. Furthermore, differences in age-related telomere attrition were established between short-lived and long-lived organisms. However, whether telomere length is a “biological thermometer” that reflects the biological state at a certain point in life or a biomarker that can influence biological conditions, delay senescence and promote longevity is still an ongoing debate. We cross-sectionally tested telomere length in different tissues of two long-lived (naked mole-rat and Spalax) and two short-lived (rat and mice) species to tease out this enigma. While blood telomere length of the naked mole-rat (NMR) did not shorten with age but rather showed a mild elongation, telomere length in three tissues tested in the Spalax declined with age, just like in short-lived rodents. These findings in the NMR, suggest an age buffering mechanism, while in Spalax tissues the shortening of the telomeres are in spite of its extreme longevity traits. Therefore, using long-lived species as models for understanding the role of telomeres in longevity is of great importance since they may encompass mechanisms that postpone aging.

Immune checkpoint blockade (ICB) has transformed cancer treatment, but success rates remain limited. Recent research suggests that dietary fiber enhances ICB efficacy through microbiome-dependent mechanisms. However, prior studies in mice compared grain-based chow (high fiber) with low–fiber-purified diet, but these diets also differed in other dimensions, including phytochemicals. Therefore, further work is needed to establish the robustness of the effect of fiber on ICB across cancer types and dietary contexts. In this study, we investigated gut microbiome composition, metabolite levels, and ICB activity in mice fed with grain-based chow or purified diets with differing quantities of isolated fibers (cellulose and inulin). Compared with dietary fiber content, consumption of chow versus purified diet had a greater effect on the gut microbiome and a much stronger impact on the metabolome. Studies in multiple tumor models revealed that fiber has a weaker impact on ICB (anti–PD-1) efficacy than previously reported. Although diet affected ICB in some models, the effect was not directionally consistent. None of the models tested displayed the pattern expected if fiber controlled ICB efficacy: strong efficacy in both chow and high–fiber-purified diet but low efficacy in low–fiber-purified diet. Thus, dietary fiber seems to have limited or inconsistent effects on ICB efficacy in mouse models, and other dietary factors that correlate with fiber intake may underlie clinical correlations between fiber consumption and immunotherapy efficacy. Significance: Clinical associations between high-fiber diets and improved immunotherapy efficacy may be driven by dietary factors correlated with fiber intake rather than fiber itself, which could impact dietary recommendations for patients undergoing immunotherapy.

The Turkana pastoralists of Kenya inhabit arid, water-limited environments and rely largely on livestock for subsistence. Working with Turkana communities, we sequenced 367 whole genomes and identified eight regions with evidence for recent positive selection. One of these regions includes a putative regulatory element for STC1 —a kidney-expressed gene involved in metabolism and the response to dehydration. We show that STC1 is induced by antidiuretic hormone in human cells, is associated with urea levels in the Turkana themselves, and is under strong and recent selection in this population as well as a second East African population, the Daasanach. This work highlights how integrating anthropological and genomic approaches can lead to a new understanding of human physiology with biomedical relevance.

Mice overexpressing Sirt6 or fed a caloric restriction (CR) diet live longer with improved health. CR increases Sirt6 levels, and its beneficial effects are mediated by the gasotransmitter H ₂ S, a one-carbon pathway product. Yet, the role of this pathway in Sirt6-regulated longevity remains elusive. Here, we show that Sirt6 controls hepatic one-carbon metabolism, preventing the aging-dependent H ₂ S reduction, and the elevation of the methyl donor, S-adenosylmethionine (SAM). Sirt6 downregulates Slc7a11 expression in an Sp1-dependent manner, decreasing cystine uptake and increasing Cgl H ₂ S production activity. Additionally, comparative acetylome in old livers revealed Sirt6-related differential acetylation of most of the one-carbon enzymes. Specifically, Sirt6-dependent Matα1 K235 deacetylation reduces its SAM production activity and Cbs binding, thereby reducing its activation of Cbs-dependent H ₂ S production. The net outcome is H ₂ S and SAM levels as observed in young animals. Thus, we unveil a fundamental mechanism for the promotion of healthy longevity by Sirt6.