Systems-level patterns in biological processes are changed under prolongevity interventions and across biological age

Abstract

Aging manifests as progressive deterioration in cellular and systemic homeostasis, requiring systems-level perspectives to understand the gradual molecular dysregulation of underlying biological processes. Here, we report systems-level changes in the molecular regulation of biological processes under multiple lifespan-extending interventions in mice and across age in humans. In mouse cohorts, Differential Rank Conservation (DIRAC) analyses of liver proteomics and transcriptomics show that mechanistically distinct prolongevity interventions tighten the regulation of aging-related biological modules, including fatty acid metabolism and inflammation processes. An integrated analysis of liver transcriptomics with mouse genome-scale metabolic model supports the shifts in fatty acid metabolism. Additionally, the difference in DIRAC patterns between proteins and transcripts suggests biological modules which may be tightly regulated via cap-independent translation. In a human cohort spanning the majority of the adult lifespan, DIRAC analyses of blood proteomics and metabolomics demonstrate that regulation of biological modules does not monotonically loosen with age; instead, the regulatory patterns shift according to both chronological and biological ages. Our findings highlight the power of systems-level approaches to identifying and characterizing the biological processes involved in aging and longevity.

The effects of 17α-estradiol treatment on endocrine system revealed by single-nucleus transcriptomic sequencing of hypothalamus

“…Previous studies have shown that 17α-estradiol extends the lifespan of male mice, has beneficial effects on metabolism and inflammation with a similar mechanism as that of rapamycin and acarbose [6][7][8]. Further investigations revealed certain unique features of 17α-estradiol in life extension distinct to rapamycin and acarbose [9,10]. Further, 17α-estradiol was shown to target hypothalamic POMC neurons to reduce metabolism by decreasing feeding behavior via anorexigenic pathways [11].…”