For decades, depression has been unfairly dismissed as "overthinking" or "personal weakness." However, a groundbreaking study published in Transl Psychiatry reshapes this narrative: depression may originate from an intracellular "energy deficit," triggered by the synergistic interaction between early life trauma and genetic vulnerability in the NAD+/SIRT1 metabolic pathway. This first-of-its-kind human research uncovers the biological underpinnings of depression, offering a novel framework for supporting mental health through metabolic regulation.ic interaction between early life trauma and genetic vulnerability in the NAD+/SIRT1 metabolic pathway. This first-of-its-kind human research uncovers the biological underpinnings of depression, offering a novel framework for supporting mental health through metabolic regulation. The Cellular Stress-Resilience Axis: NAD+ and SIRT1
To contextualize the breakthrough, two key molecular players in cellular homeostasis deserve emphasis:

• NAD+: Referred to as the "fuel of youth" in scientific discourse, nicotinamide adenine dinucleotide (NAD+) is a ubiquitous coenzyme critical for mitochondrial ATP synthesis—the primary energy source for cells. Insufficient NAD+ levels impair cellular energy production, including in neurons responsible for mood regulation and reward processing.
• SIRT1: A NAD+-dependent deacetylase (often categorized as a "longevity and repair protein"), SIRT1 mediates DNA repair, modulates inflammatory responses, and maintains the integrity of the brain’s reward system (nucleus accumbens). Its functionality is strictly contingent on adequate NAD+ availability, forming a synergistic "stress-resistance pathway" within the body.

Together, this axis serves as a built-in defense against environmental stressors—until genetic predisposition and early life adversity disrupt its balance.
The Pathogenic Cascade: Human Evidence and Preclinical Validation
Human Study Findings (100,000+ UK Biobank Participants)
Researchers identified a clear causal pathway in human subjects:Early life stress (emotional neglect, abuse, or chronic adversity) → Activation of NAD+/SIRT1 high-risk genetic variants → Significant reduction in cellular NAD+ levels → Compromised SIRT1 activity → Dysregulated functional connectivity between the nucleus accumbens and prefrontal cortex → Manifestation of anhedonia and depressive symptoms.
 

Preclinical (Murine) Study Confirmation & Cross-Validation
Complementary preclinical research published in Science Advances corroborated this mechanism:Male mice exposed to early life stress exhibited reduced SIRT1 expression in the nucleus accumbens and displayed depression-like behaviors, including social withdrawal and diminished motivation. Administration of an NAD+ precursor (NMN) restored NAD+ concentrations, reactivated SIRT1 function, and reversed the observed depressive phenotypes.

Notably, the human study’s key findings align perfectly with the preclinical results: just as the murine experiment observed significant effects exclusively in male mice, the human data confirmed the synergistic effect of early life stress and NAD+/SIRT1 genetic risk elevates depression susceptibility only in males, with no meaningful association in females. This cross-species consistency strongly suggests fundamental sex differences in the biological pathways underlying depression—highlighting that metabolic dysfunction via the NAD+/SIRT1 axis is a male-specific driver of depression risk.


Key Research Conclusions
1. Sex-Specific Biological Pathway
The convergence of human and preclinical evidence confirms a critical conclusion: males and females differ fundamentally in the metabolic mechanisms linking early life stress to depression. For males, the NAD+/SIRT1 pathway acts as a key mediator—whereas this pathway does not contribute meaningfully to female depression susceptibility. This finding challenges the one-size-fits-all approach to mental health research and intervention, underscoring the need for gender-tailored strategies.
2. Independence from Body Fat: A Definitive Finding
Contrary to conventional assumptions linking stress-induced adiposity to depression, the human study delivered a clear conclusion: the NAD+/SIRT1 pathway’s role in driving depression is entirely independent of body fat percentage. While early life stress may indirectly contribute to depression via increased adiposity in some individuals, the research confirms that metabolic dysfunction in the NAD+/SIRT1 axis operates as a direct, standalone driver. Regardless of weight, individuals with high-risk genetic profiles and a history of childhood trauma face elevated depression risk—pinpointing cellular energy depletion, not body composition, as the core issue.
A Novel Direction for Mental Health Support: Targeting Cellular Energy Metabolism
Given the central role of NAD+ depletion in the identified pathway—validated across human and preclinical models—NAD+ precursors such as NADH and NMN represent promising tools for supporting mental resilience. NADH, the reduced and biologically active form of NAD+, offers a direct route to replenishing cellular NAD+ stores—bypassing multiple conversion steps required by other precursors and enabling rapid energy restoration.
For male populations with a history of childhood trauma or NAD+/SIRT1 genetic vulnerability, maintaining optimal NAD+ levels may help strengthen the brain’s stress resilience, consistent with preclinical evidence showing reversal of depressive phenotypes. Importantly, this approach does not constitute a "cure for depression" but rather a complementary strategy to address the well-validated metabolic underpinnings of vulnerability—aligning with the emerging paradigm of precision psychiatry.
Rethinking Depression: From Stigma to Biological Understanding
This research challenges the persistent stigma surrounding depression by framing it as a condition rooted in measurable biological mechanisms, not personal inadequacy. Early life experiences leave enduring 印记 on cellular metabolism, while genetic factors modulate individual susceptibility to these environmental triggers—with males uniquely vulnerable to disruptions in the NAD+/SIRT1 axis.
By validating the NAD+/SIRT1 pathway as a male-specific driver of depression (consistently across human and animal models), the study provides a definitive biological target for future interventions. As research continues to unravel the sex-specific complexities of mental health, NAD+ precursors stand out as a promising avenue to enhance cellular resilience against stress-induced depression—offering hope for more personalized, effective support strategies.

References

1. Torok D, Krause S, Gecse K, et al. Interaction of early life stress and NAD + /SIRT1 pathway genetic risk promotes depression. Transl Psychiatry. 2025 Nov 12. doi: 10.1038/s41398-025-03733-5. (Human study)
2. Morató L, Astori S, Zalachoras I, et al. eNAMPT actions through nucleus accumbens NAD+/SIRT1 link increased adiposity with sociability deficits programmed by peripuberty stress. Sci Adv. 2022; 8: eabj9109. (Preclinical murine study)