Metabolic dysdifferentiation as the primary driver of aging: A proposal for NAD + precursor and mTOR modulator synergy to restore cellular identity

Aging is the gradual decline of organismal homeostasis and health. While numerous hallmarks of aging have been recognized, a unifying, causative mechanism remains elusive. We propose a novel concept termed “metabolic dysdifferentiation.” We will show how aging-related alterations in central metabolic pathways, particularly the decline of nicotinamide adenine dinucleotide (NAD + ) and dysregulation of the mechanistic target of rapamycin (mTOR), lead to the collapse of tightly tuned epigenetic and transcriptional programs that dictate maintenance of cellular identity. This gives rise to a dedifferentiated, functionally ill-defined cellular state that modifies both the health and overall resilience of tissues. We hypothesize that concurrent administration of NAD + precursors (e.g., nicotinamide mononucleotide, NMN) and mTOR modulators (e.g., rapamycin analogs) can fill in these metabolic gaps to mitigate the epigenetic decline, restore proteostasis, and relink transcriptional fidelity with cell-type-specific gene activation. Here we present a complete conceptual and practical foundation of this hypothesis along with the synthesis of previous data from genomics, metabolomics and interventional studies. We describe mathematical network models of NAD + –mTOR interactions, suggest unique combination therapy regimens, and highlight experimental strategies for validation using multi-omics in model organisms and human cell systems. Our model accounts for aging as a loss of systemic metabolic information instead of damage accumulation, providing a unique and actionable framework for therapeutic impact.