Baur, Joseph A.

Abstract The aging process is universal, and it is characterized by a progressive deterioration and decrease in physiological function leading to decline on the organismal level. Nevertheless, a number of genetic and nongenetic interventions have been described, which successfully extend healthspan and lifespan in different species. Furthermore, a number of clinical trials have been evaluating the feasibility of different interventions to promote human health. The goal of the annual Biological Sciences Section of the Gerontological Society of America meeting was to share current knowledge of different topics in aging research and provide a vision of the future of aging research. The meeting gathered international experts in diverse areas of aging research including basic biology, demography, and clinical and translational studies. Specific topics included metabolism, inflammaging, epigenetic clocks, frailty, senescence, neuroscience, stem cells, reproductive aging, inter-organelle crosstalk, comparative transcriptomics of longevity, circadian clock, metabolomics, and biodemography.

Abstract The geroscience hypothesis posits that by targeting key hallmarks of aging we may simultaneously prevent or delay several age-related diseases and thereby increase healthspan, or life span spent free of significant disease and disability. Studies are underway to examine several possible pharmacological interventions for this purpose. As part of a National Institute on Aging workshop on the development of function-promoting therapies, scientific content experts provided literature reviews and state-of-the-field assessments for the studies of senolytics, nicotinamide adenine dinucleotide (NAD+) boosters, and metformin. Cellular senescence increases with age, and preclinical studies demonstrate that the use of senolytic drugs improves healthspan in rodents. Human studies using senolytics are in progress. NAD+ and its phosphorylated form, NADP+, play vital roles in metabolism and cellular signaling. Increasing NAD+ by supplementation with precursors including nicotinamide riboside and nicotinamide mononucleotide appears to extend healthspan in model organisms, but human studies are limited and results are mixed. Metformin is a biguanide widely used for glucose lowering, which is believed to have pleiotropic effects targeting several hallmarks of aging. Preclinical studies suggest it improves life span and healthspan, and observational studies suggest benefits for the prevention of several age-related diseases. Clinical trials are underway to examine metformin for healthspan and frailty prevention. Preclinical and emerging clinical studies suggest there is potential to improve healthspan through the use of pharmacologic agents reviewed. However, much further research is needed to demonstrate benefits and general safety for wider use, the appropriate target populations, and longer-term outcomes.

Abstract Chemotherapy-induced cognitive impairment (CICI) is often reported as a neurotoxic side effect of chemotherapy. Although CICI has emerged as a significant medical problem, meaningful treatments are not currently available due to a lack of mechanistic understanding underlying CICI pathophysiology. Using the platinum-based chemotherapy cisplatin as a model for CICI, we show here that cisplatin suppresses nicotinamide adenine dinucleotide (NAD+) levels in the adult female mouse brain in vivo and in human cortical neurons derived from induced pluripotent stem cells in vitro. Increasing NAD+ levels through nicotinamide mononucleotide (NMN) administration prevented cisplatin-induced abnormalities in neural progenitor proliferation, neuronal morphogenesis, and cognitive function without affecting tumor growth and antitumor efficacy of cisplatin. Mechanistically, cisplatin inhibited expression of the NAD+ biosynthesis rate-limiting enzyme nicotinamide phosphoribosyl transferase (Nampt). Selective restoration of Nampt expression in adult-born neurons was sufficient to prevent cisplatin-induced defects in dendrite morphogenesis and memory function. Taken together, our findings suggest that aberrant Nampt-mediated NAD+ metabolic pathways may be a key contributor in cisplatin-induced neurogenic impairments, thus causally leading to memory dysfunction. Therefore, increasing NAD+ levels could represent a promising and safe therapeutic strategy for cisplatin-related neurotoxicity. Significance: Increasing NAD+ through NMN supplementation offers a potential therapeutic strategy to safely prevent cisplatin-induced cognitive impairments, thus providing hope for improved quality of life in cancer survivors.