Nayeri Rad, A. | Search bioRxiv

bioRxiv2026

NAMPT activation uncovers a senescence-specific vulnerability and promotes healthy aging in combination with NAM

Aging is driven by multiple interacting processes, suggesting that effective strategies to promote healthy aging may require simultaneous targeting of more than one underlying mechanism. Here we identify a strategy that couples restoration of nicotinamide adenine dinucleotide (NAD+) homeostasis with selective targeting of senescent cells, two mechanistically linked features of aging. Senescent cells express elevated intracellular levels of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the nicotinamide (NAM) salvage pathway for NAD+ biosynthesis. Despite increased NAMPT abundance, isotope-tracing studies revealed decreased NAD+ biosynthesis and consumption, indicating that elevated NAMPT abundance was not accompanied by a corresponding increase in NAD+ metabolic flux. Treatment with the NAMPT activator SBI-0802162 engaged the spare enzymatic capacity of NAMPT in senescent cells and produced a marked rise in intracellular NAD+ that, when sustained, disrupted their transcriptional program and selectively reduced the viability of senescent cells but not proliferating cells. In mice, SBI-0802162 reduced circulating NAM levels, suggesting that sustained NAMPT activation may be limited by substrate availability. This observation prompted the development of a combination approach using SBI-0802162 together with dietary NAM supplementation. Co-administration of SBI-0802162 and NAM robustly increased tissue NAD+, suppressed select age-associated inflammatory signatures and markers of cellular senescence in a tissue-specific manner. These molecular effects occurred alongside preserved physical performance in aged mice and reductions in food intake and body weight, which were observed whether SBI-0802162 was present in the chow or administered by oral gavage. Together, these findings establish a mechanistically integrated approach to target two convergent features of aging, NAD+ dysregulation and senescent cell accumulation, and support combined NAMPT activation and NAM supplementation as a strategy to promote healthy aging.

molecular biology↗

bioRxiv2024

Connectivity Map and perturbation-based sensitivity analysis identifies MEK inhibitors as senolytics in human lung fibroblasts

Recently, the elimination of the disease-associated accumulation of senescent cells using senolytics has been shown to exert health benefits in animal studies. However, due to the heterogeneity of cell senescence and its unrecognized master regulators, drug development faces a complexity that must be handled. Bioinformatic elucidation of genes and pathways involved in senolysis and prediction of senolytic activity of compounds can cut costs and facilitate faster achievements in the field. In the present investigation, after obtaining the consensus gene signature of senescent fibroblasts of lung origin and deriving its anti-apoptotic module, we utilized Connectivity Map (CMap) alongside small molecule and genetic perturbation sensitivity data in cancer cell lines to identify drugs and genetic interventions that might induce apoptosis or sensitize senescent cells to apoptosis. Through bioinformatic evaluations, we speculate that activation of early stages of autophagy which contributes to the formation of autophagosomes, concurrent with the activation of waste protein concealment system by the mean of p62 and chaperoning system alongside an increase in JUNB gene expression can secure the survival of the senescent cells even when homeostasis of different cellular processes is disrupted. Moreover, our bioinformatic evaluation proposed selumetinib, a MEK inhibitor, as a senolytic against senescent lung fibroblasts. The senolytic activity of a variety of MEK inhibitors in senescent lung fibroblasts was confirmed using human lung fibroblasts in vitro.

pharmacology and toxicology↗