Alpha-ketoglutarate, an endogenous metabolite, extends lifespan and compresses morbidity in aging mice

Abstract

The decline in early life mortality since the 1950s has resulted in dramatic demographic shift towards aged population. Aging manifests as a decline in health, multiple organ dysfunction and increased vulnerability to diseases, which degrades quality of life. A verity of genetic and pharmacological interventions, mostly from non-vertebrate models, have been identified that can enhance lifespan. Whether these interventions extend healthspan, the disease free and functional period of life, has only sometimes been tested and is often a matter of debate. Human aging indices have been developed to assess elements of functional decline with aging (e.g. sarcopenia, cognitive function). However, corresponding comprehensive indices in mice are seldom applied to aging studies. To probe the relationship between healthspan and lifespan extension in mammals, we performed a series of longitudinal, clinically-relevant healthspan measurements.Metabolism and aging are tightly connected and specific perturbations of nutrient-sensing pathways can enhance longevity in laboratory animals. Here we show that alpha-ketoglutarate (delivered in the form of a Calcium salt, CaAKG), a key metabolite in tricarboxylic (TCA) cycle that is reported to extend lifespan in worms , can significantly extend lifespan and healthspan in mice. AKG is involved in various fundamental processes including collagen synthesis and epigenetic changes. Due to its broad roles in multiple biological processes, AKG has been a subject of interest for researchers in various fields. AKG also influences several age-related processes, including stem cell proliferation and osteoporosis. To determine its role in mammalian aging, we administered CaAKG in 18 months old mice and determined its effect on the onset of frailty and survival, discovering that the metabolite promotes longer, healthier life associated with a decrease in levels of inflammatory factors. Interestingly the reduction in frailty was more dramatic than the increase in lifespan, leading us to propose that CaAKG compresses morbidity.

Emerging Insights into the Metabolic Alterations in Aging Using Metabolomics

“…This study further identified several metabolic pathways that were enriched with metabolites changes, including the sugar and glycerophospholipid metabolism, amino acids, neurotransmitters, and carnitine shuttle [79]. Interestingly, a key tricarboxylic acid cycle (TCA) intermediate metabolite α-ketoglutarate was recently shown to extend lifespan in worms, flies, and mice, which suggested that longevity pathways might be evolutionarily conserved [82][83][84][85].…”

Resilience in a Natural Model of Metabolic Dysfunction Through Changes in Longevity and Ageing-Related Metabolites

“…(B) Glutathione, another antioxidant, is significantly increased in the liver and brain under 30-day fasting. Alpha-ketoglutarate is a tricarboxylic acid cycle (TCA) intermediate that has been linked to longevity in nematodes and mice (18, 19). (C) Nicotinamide is a precursor to NAD + synthesis via a salvage pathway, and increased in the liver but decreased in other tissues in cavefish.…”

NAD+ Metabolism Regulates Preadipocyte Differentiation by Enhancing α-Ketoglutarate-Mediated Histone H3K9 Demethylation at the PPARγ Promoter

“…It has been reported that αKG administration extends the adult lifespan of C. elegans by ATP synthase-TOR axis (Chin et al, 2014). Long-term supplementation of αKG also extends the healthspan in mice by reducing the chromic inflammation (Asadi Shahmirzadi et al, 2020). αKG supplementation also improved the energy expenditure by promoting UCP1 expression (Tian et al, 2020).…”