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.

Evidence for Biological Age Acceleration and Telomere Shortening in COVID-19 Survivors

“…The progression of aging is associated with critical metabolic changes. Some of these changes occur at the level of metabolites regulating the function of essential epigenetic enzymes, such as the decrease in NAD+ levels, the cofactor of sirtuins [ 41 ], and the reduction in alpha-ketoglutaric acid [ 42 ], the cofactor for all dioxygenases [ 43 ]. Although very speculative, it may be that older adults are relatively less sensitive to SARS-CoV-2-dependent epigenetic changes due to changes in their metabolic landscape.…”

ARDD 2020: from aging mechanisms to interventions

“…Aging interventions would benefit most by applying prevention-based approaches and biomarker discovery [109]. Understanding how different physiological measures and aging clocks correspond to each other could allow targeted testing of different types of aging interventions, including the recently published life-extending molecule 2-oxoglutarate [110]. Further, João Pedro de Magalhães, University of Liverpool, UK, touched upon the topic of longevity interventions and highlighted the exponential growth of pharmacological approaches (DrugAge database), while research in genes associated with longevity have plateaued in recent years (GenAge database).…”

Serotonin signaling modulates aging-associated metabolic network integrity in response to nutrient choice in Drosophila melanogaster

“…The αKG/glutamine synthesis pathways may also be important in modulating the ability of diet restriction to increase lifespan 19 . More recently, it has been shown that the lifespan-extending effects of αKG are preserved in both flies 52 and mice 53 . In the future, it is imperative to investigate the impact of these metabolites and metabolic pathways on network structures and metabolic communications, and to better understand the mechanisms through which nutrient presentation influences lifespan.…”