Significant progress in clinical care has extended human life expectancy to unprecedented levels. However, this trend has been parallelled by a rise in years lived with poor health, posing profound challenges not only to individual quality of life, but also to substantial medical and socioeconomic burdens at the population level. This underscores the urgent need for strategies that extend healthspan alongside lifespan. In this regard, nicotinamide adenine dinucleotide (NAD⁺) has emerged as a central metabolic cofactor and signaling molecule that regulates processes fundamental to health and longevity, including energy metabolism, mitochondrial function, inflammation, and DNA repair. Importantly, intracellular NAD⁺ levels decline with age across multiple tissues and organ systems, and restoring NAD⁺ content has been shown to reinstate cellular and physiological function in various model systems. Among the strategies to augment NAD⁺, supplementation with its precursors, namely nicotinic acid/niacin, nicotinamide, nicotinamide riboside, and nicotinamide mononucleotide, represents the most practical and extensively studied approach. Over the past two decades, preclinical research and an increasing number of clinical trials have investigated the therapeutic potential of these precursors in preventing or reversing age-associated decline and pathologies. In this review, we synthesize recent clinical advances, critically evaluate the promise and limitations of NAD⁺ precursor supplementation, and discuss future directions for leveraging NAD⁺ metabolism to improve healthspan in a rapidly aging global population.

The biology of aging is increasingly understood through geroscience frameworks integrating molecular, cellular, physiological, and social hallmarks. Recently, we introduced psychosocial factors including mental illness as an important hallmark of aging. Indeed, exposome-centered approaches reveal complex interactions among socioeconomic, environmental, behavioral, and genomic factors. Precision Geromedicine aims to target all these determinants in a holistic fashion to improve aging trajectories and extend healthspan.

In recent years, the terms “gerosuppressors” and “gerogenes” have been introduced to describe factors that respectively delay or accelerate aging. These factors are present across various cell types. Specific proteins, such as tau predominantly expressed in neurons, may act as neuron-specific gerosuppressors or gerogenes. Tau exhibits a dual role influenced by its post-translational modifications, particularly phosphorylation. In this review, we discuss relevant examples of tau isoforms that demonstrate both roles, underscoring its dual influence on neuronal aging.