Cellular senescence is a state of irreversible cellular growth arrest accompanied by distinct changes in gene expression and the acquisition of a complex proinflammatory secretory profile termed the senescence-associated secretory phenotype (SASP). Senescent cells accumulate in aged tissues and contribute to age-related disease in mice. Increasing evidence that selective removal of senescent cells can ameliorate diseases of late life and extend lifespan in mice has given rise to the development of senolytics that target senescent cells as anti-aging therapeutics. To realize the full potential of senolytic medicine, robust biomarkers of senescence must be in place to monitor the in vivo appearance of senescent cells with age, as well as their removal by senolytic treatments. Here we investigate the dynamic changes in expression of the molecular hallmarks of senescence, including p16Ink4a, p21Cip1, and SASP factors in multiple tissues in mice during aging. We show that expression of these markers is highly variable in age- and tissue-specific manners. Nevertheless, Mmp12 represents a robust SASP factor that shows consistent age-dependent increases in expression across all tissues analyzed in this study and p16Ink4a expression is consistently increased with age in most tissues. Likewise, in humans CDKN2A (p16Ink4a) is one of the top genes exhibiting elevated expression in multiple tissues with age as revealed by data analysis of the Genotype-Tissue Expression (GTEx) project. These results support the targeting of p16Ink4a expressing-cells in senolytic treatments, while emphasizing the need to establish a panel of robust biomarkers of senescence in vivo in both mice and humans.
SUMMARY
A hallmark of aging is a decline in metabolic homeostasis, which is
attenuated by dietary restriction (DR). However, the interaction of aging and DR
with the metabolome is not well understood. We report that DR is a stronger
modulator of the rat metabolome than age in plasma and tissues. A comparative
metabolomic screen in rodents and humans identified circulating sarcosine as
being similarly reduced with aging and increased by DR, while sarcosine is also
elevated in long-lived Ames dwarf mice. Pathway analysis in aged
sarcosine-replete rats identify this biogenic amine as an integral node in the
metabolome network. Finally, we show that sarcosine can activate autophagy in
cultured cells and enhances autophagic flux in vivo, suggesting
a potential role in autophagy induction by DR. Thus, these data identify
circulating sarcosine as a biomarker of aging and DR in mammalians and may
contribute to age-related alterations in the metabolome and in proteostasis.
Sirtuin 6 (SIRT6) is a deacylase and mono‐ADP ribosyl transferase (mADPr) enzyme involved in multiple cellular pathways implicated in aging and metabolism regulation. Targeted sequencing of SIRT6 locus in a population of 450 Ashkenazi Jewish (AJ) centenarians and 550 AJ individuals without a family history of exceptional longevity identified enrichment of a SIRT6 allele containing two linked substitutions (N308K/A313S) in centenarians compared with AJ control individuals. Characterization of this SIRT6 allele (centSIRT6) demonstrated it to be a stronger suppressor of LINE1 retrotransposons, confer enhanced stimulation of DNA double‐strand break repair, and more robustly kill cancer cells compared with wild‐type SIRT6. Surprisingly, centSIRT6 displayed weaker deacetylase activity, but stronger mADPr activity, over a range of NAD+ concentrations and substrates. Additionally, centSIRT6 displayed a stronger interaction with Lamin A/C (LMNA), which was correlated with enhanced ribosylation of LMNA. Our results suggest that enhanced SIRT6 function contributes to human longevity by improving genome maintenance via increased mADPr activity and enhanced interaction with LMNA.
Drosophila species lack most hallmarks of adaptive immunity yet are highly successful against an array of natural microbial pathogens and metazoan enemies. When attacked by figitid parasitoid wasps, fruit flies deploy robust, multi-faceted innate immune responses and overcome many attackers. In turn, parasitoids have evolved immunosuppressive strategies to match, and more frequently to overcome, their hosts. We present methods to examine the evolutionary dynamics underlying anti-parasitoid host defense by teasing apart the specialized immune-modulating venoms of figitid parasitoids and, in turn, possibly delineating the roles of individual venom molecules. This combination of genetic, phylogenomic, and "functional venomics" methods in the Drosophila-parasitoid model should allow entomologists and immunologists to tackle important outstanding questions with implications across disciplines and to pioneer translational applications in agriculture and medicine.
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