Longevity‐related molecular pathways are subject to midlife “switch” in humans

Abstract

Emerging evidence indicates that molecular aging may follow nonlinear or discontinuous trajectories. Whether this occurs in human neuromuscular tissue, particularly for the noncoding transcriptome, and independent of metabolic and aerobic capacities, is unknown. Applying our novel RNA method to quantify tissue coding and long noncoding RNA (lncRNA), we identified ~800 transcripts tracking with age up to ~60 years in human muscle and brain. In silico analysis demonstrated that this temporary linear “signature” was regulated by drugs, which reduce mortality or extend life span in model organisms, including 24 inhibitors of the IGF‐1/PI3K/mTOR pathway that mimicked, and 5 activators that opposed, the signature. We profiled Rapamycin in nondividing primary human myotubes (n = 32 HTA 2.0 arrays) and determined the transcript signature for reactive oxygen species in neurons, confirming that our age signature was largely regulated in the “pro‐longevity” direction. Quantitative network modeling demonstrated that age‐regulated ncRNA equaled the contribution of protein‐coding RNA within structures, but tended to have a lower heritability, implying lncRNA may better reflect environmental influences. Genes ECSIT, UNC13, and SKAP2 contributed to a network that did not respond to Rapamycin, and was associated with “neuron apoptotic processes” in protein–protein interaction analysis (FDR = 2.4%). ECSIT links inflammation with the continued age‐related downwards trajectory of mitochondrial complex I gene expression (FDR < 0.01%), implying that sustained inhibition of ECSIT may be maladaptive. The present observations link, for the first time, model organism longevity programs with the endogenous but temporary genome‐wide responses to aging in humans, revealing a pattern that may ultimately underpin personalized rates of health span.

Multi-omics network analysis reveals distinct stages in the human aging progression in epidermal tissue

“…Notably, the most prominent global pattern was a sharp loss in predictivity observed in the transition from aging phase 3 to aging phase 4 in many pathways. In line with the loss of predictivity in nutrient sensing signaling hallmark observed in the HoA analysis and recent reports [14], mTOR-related signaling was among the pathways undergoing this distinct transition in the transition from phase 3 to phase 4 ( Figure 5B), which, biological age outliers aside, matches the chronological age threshold of 60 identified in recent reports [14].…”

“…One of the pathways that notably lost predictivity at the beginning of aging phase 4 was PI3K-mTOR-signaling, a known longevity-associated pathway, whose regulation has recently been reported to be largely lost around the chronological age of 60 [14]. Among the other pathways affected by a similar decrease in pathway enrichment were also DNA repair pathways.…”

“…As our analyses on the succession of the HoA already indicated a distinct shift in predictivities towards phase 4 of the identified aging stages, and in light of the recent publication of a sharp loss of signature identity for longevity-associated mTOR-signaling in human tissue around 60 years [14], we decided to expand our pathway analysis and explore the mid-to-late-life transition in more detail. For this we utilized the hallmark gene sets defined by the Broad Institute into the analysis, a set of conserved and highly refined gene sets created to improve pathway inference by reducing variance and gene overlap [20].…”

“…More recently, evidence of the existence of non-linear switches, capable of extending model animal lifespan in vivo, has been presented concerning mitochondrial function, further implicating discontinuous biological processes in aging [13]. Not long ago now, the report of a mid-life switch involving a longevity-associated signaling pathway in aging human muscle and brain tissue was published [14]. Using gene and long non-coding RNA expression profiling, the authors observed that an age-related IGF-1/PI3K/mTOR-related RNA response signature was essentially lost with the start of the sixth decade of life.…”

Mild depolarization of the inner mitochondrial membrane is a crucial component of an anti-aging program

“…The participation of mROS and Complex I in aging has received increasing attention in recent years (e.g., ref. 21). Our concept of the aging program is based on the assumption that mROS (the levels of which increase with age) function as a poison that causes chronic phenoptosis (9).…”