NAD+ in aging, metabolism, and neurodegeneration

This review published in Science by Eric Verdin of the Buck Institute for Research on Aging consolidated the role of NAD+ as a key molecule in the biology of aging and proposed that restoring NAD+ levels could have therapeutic impact on multiple age-associated diseases. The article became a fundamental reference in the field.

Verdin presented compelling evidence that the progressive decline of NAD+ with age is an evolutionarily conserved phenomenon that directly contributes to multiple pathologies:

• Mitochondrial dysfunction: The drop in NAD+ reduces SIRT3 activity in mitochondria, compromising the respiratory chain and increasing oxidative stress
• Neurodegeneration: Low NAD+ levels impair neuronal DNA repair and accelerate axonal degeneration
• Metabolic decline: Reduced nuclear SIRT1 compromises the adaptive response to metabolic stress
• Chronic inflammation: CD38 activation by inflammatory cytokines consumes NAD+, creating a cycle of "inflammaging"

The review highlighted promising preclinical data with NAD+ precursors: supplementation with NMN and NR in animal models reversed aspects of muscle aging, improved mitochondrial function, protected against neurodegeneration, and restored insulin sensitivity. The effects were particularly notable in Alzheimer's and Parkinson's disease models.

Verdin argued that NAD+ represents a unique therapeutic target because it sits at the intersection of multiple aging pathways, and that restoring its levels could have systemic beneficial effects, unlike interventions targeting a single pathological pathway.