Abstract
Determinants of length of life are not well understood, and therefore increasing lifespan is a challenge. Cardinal theories of aging suggest that oxidative stress (OxS) and mitochondrial dysfunction contribute to the aging process, but it is unclear if they could also impact lifespan. Glutathione (GSH), the most abundant intracellular antioxidant, protects cells from OxS and is necessary for maintaining mitochondrial health, but GSH levels decline with aging. Based on published human studies where we found that supplementing glycine and N-acetylcysteine (GlyNAC) improved/corrected GSH deficiency, OxS and mitochondrial dysfunction, we hypothesized that GlyNAC supplementation could increase longevity. We tested our hypothesis by evaluating the effect of supplementing GlyNAC vs. placebo in C57BL/6J mice on (a) length of life; and (b) age-associated GSH deficiency, OxS, mitochondrial dysfunction, abnormal mitophagy and nutrient-sensing, and genomic-damage in the heart, liver and kidneys. Results showed that mice receiving GlyNAC supplementation (1) lived 24% longer than control mice; (2) improved/corrected impaired GSH synthesis, GSH deficiency, OxS, mitochondrial dysfunction, abnormal mitophagy and nutrient-sensing, and genomic-damage. These studies provide proof-of-concept that GlyNAC supplementation can increase lifespan and improve multiple age-associated defects. GlyNAC could be a novel and simple nutritional supplement to improve lifespan and healthspan, and warrants additional investigation.
Highlights
Factors responsible for increasing length of life are not well understood
Because glycine and N-acetylcysteine (GlyNAC) supplementation improves multiple key defects associated with human aging, we hypothesized that GlyNAC supplementation could improve longevity by improving GSH deficiency, oxidative stress (OxS), mitochondrial dysfunction, abnormalities in mitophagy and nutrient sensing, and genomic damage at the organ level
We reported that similar defects existand in older adults (OA) in terms of GSH deficiency, increased OxS, mitochondrial dysfunction and genomic damage, and that a longer duration of supplementation with GlyNAC for
Summary
Factors responsible for increasing length of life are not well understood. there is a growing quest to slow aging via drug discovery [1], identifying effective interventions to increase lifespan remain a challenge. Clues to unravel the mystery of longevity come from factors identified as contributors to the biology of the aging process such as elevated oxidative stress (OxS) and mitochondrial dysfunction, which were proposed decades ago as cardinal theories of aging [2,3]. Elevated OxS is inherently toxic to cellular and organ health [4–19], and its damaging potential is further amplified by the deficiency of the endogenous antioxidant glutathione (GSH). We discovered and reported that supplementing GlyNAC (glycine and N-acetylcysteine, as a cysteine donor) in human trials corrected GSH deficiency, OxS and mitochondrial dysfunction, and in HIV-patients it improved mitophagy, nutrient sensing and lowered genomic damage, and reversed premature aging [29,30]. Because GlyNAC supplementation improves multiple key defects associated with human aging, we hypothesized that GlyNAC supplementation could improve longevity by improving GSH deficiency, OxS, mitochondrial dysfunction, abnormalities in mitophagy and nutrient sensing, and genomic damage at the organ level
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