The NAD⁺–Insulin–AMPK–mTOR Axis: A Systems Biology Framework Linking Metabolic Dysregulation to Aging, Neurodegeneration, and Chronic Disease (2026)
Abstract
Background: Aging and major chronic diseases—including type 2 diabetes, cardiovascular disease, neurodegeneration, and certain cancers—share overlapping metabolic abnormalities. Emerging evidence suggests that disturbances in redox balance (NAD⁺/NADH), insulin signaling, and nutrient-sensing pathways (AMPK and mTOR) may represent convergent upstream mechanisms.
Objective: To synthesize mechanistic and translational evidence into a unified systems biology model describing how chronic nutrient excess and impaired metabolic oscillation influence aging and disease pathogenesis.
Methods: Narrative synthesis of peer-reviewed literature across redox biology, mitochondrial physiology, insulin signaling, geroscience, and neurodegeneration. Emphasis was placed on mechanistic plausibility, human interventional data where available, and cross-disease convergence.
Results: Chronic energy surplus is associated with altered NAD⁺/NADH ratios, mitochondrial dysfunction, hyperinsulinemia, persistent mTOR activation, and suppressed autophagy. These interconnected disturbances contribute to impaired metabolic flexibility and may promote cellular senescence, neurodegeneration, and tumorigenesis. Interventions that restore metabolic oscillation—such as caloric restriction, exercise, and time-restricted feeding—activate AMPK, suppress mTOR signaling, improve insulin sensitivity, and enhance mitochondrial quality control. Human data on NAD⁺ precursor supplementation demonstrate biochemical efficacy but mixed clinical outcomes.
Conclusion: A systems-level framework centered on redox balance and nutrient sensing provides a mechanistic bridge between metabolic disease and aging biology. While causal hierarchy and therapeutic thresholds require further investigation, restoration of metabolic flexibility represents a promising unifying target for chronic disease mitigation.
Keywords
NAD⁺; insulin resistance; AMPK; mTOR; metabolic flexibility; aging; Alzheimer’s disease; mitochondrial dysfunction; hyperinsulinemia; autophagy
Introduction
Chronic diseases traditionally classified as discrete pathologies—type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD), Alzheimer’s disease (AD), obesity, and cancer—share overlapping metabolic abnormalities, including insulin resistance, mitochondrial dysfunction, and chronic low-grade inflammation. Increasingly, these conditions are conceptualized not as isolated organ failures but as manifestations of systemic metabolic dysregulation.
Investigators including Ben Bikman have emphasized hyperinsulinemia and insulin resistance as foundational disturbances preceding overt glycemic abnormalities. Concurrently, geroscience research has identified dysregulated nutrient-sensing pathways—particularly AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR)—as central regulators of lifespan and cellular resilience.
Redox biology adds another layer to this model. Age-related decline in nicotinamide adenine dinucleotide (NAD⁺) and alterations in the NAD⁺/NADH ratio influence mitochondrial respiration, sirtuin activation, and DNA repair mechanisms. These processes intersect with insulin signaling and nutrient sensing.
This review proposes an integrated framework in which chronic nutrient abundance drives persistent anabolic signaling and redox imbalance, impairing metabolic flexibility and accelerating cellular aging.
Methods
This manuscript is a narrative systems-level synthesis rather than a formal systematic review. Literature was identified through PubMed searches using combinations of the following terms:
“NAD⁺ aging”
“NADH redox insulin resistance”
“AMPK mTOR aging”
“hyperinsulinemia chronic disease”
“mitochondrial dysfunction Alzheimer’s”
“mTOR cancer metabolism”
Priority was given to:
Peer-reviewed mechanistic studies
Randomized controlled human trials where available
Foundational reviews in high-impact journals
Translational research bridging multiple disease domains
Non-peer-reviewed media sources were not used as primary evidence but may contextualize scientific discussions.
Results and Synthesis
1. NAD⁺/NADH Redox Biology and Metabolic Regulation
1.1 Biochemical Role of NAD⁺
NAD⁺ functions as:
A redox cofactor in glycolysis, TCA cycle, and β-oxidation
A substrate for sirtuins (SIRT1–7)
A substrate for poly(ADP-ribose) polymerases (PARPs)
A regulator of mitochondrial homeostasis
The NAD⁺/NADH ratio reflects cellular oxidative capacity. A high NAD⁺/NADH ratio favors oxidative metabolism and sirtuin activity; a reduced ratio may impair electron transport efficiency.
1.2 Age-Related NAD⁺ Decline
Multiple studies demonstrate reduced tissue NAD⁺ concentrations with aging, potentially mediated by:
Increased CD38 expression
Increased PARP activity due to DNA damage
Reduced NAMPT activity
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1.3 Reductive Stress and Metabolic Overload
Excess nutrient intake—particularly combined carbohydrate and fat—can increase NADH production beyond mitochondrial oxidative capacity. Accumulated NADH may:
Increase reactive oxygen species
Stabilize hypoxia-inducible factor-1α (HIF-1α)
Promote glycolytic reprogramming
This state, sometimes described as “pseudohypoxia,” resembles metabolic shifts observed in cancer and neurodegeneration.
2. Insulin Resistance and Hyperinsulinemia
2.1 Insulin as a Nutrient Signal
Insulin regulates:
Glucose uptake
Lipid storage
Protein synthesis
mTOR activation
Chronic hyperinsulinemia may precede hyperglycemia and contribute to metabolic inflexibility.
2.2 Mechanistic Pathways of Insulin Resistance
Established mechanisms include:
Lipotoxicity (DAG/ceramide accumulation)
Mitochondrial dysfunction
Inflammatory signaling (IKKβ/NF-κB activation)
Endoplasmic reticulum stress
Redox imbalance may exacerbate these processes by impairing mitochondrial efficiency.
2.3 Clinical Implications
Hyperinsulinemia is associated with increased risk of:
T2DM
Hypertension
NAFLD
Cardiovascular disease
Certain malignancies
Insulin resistance is therefore both a metabolic and systemic disorder.
3. AMPK and mTOR: Nutrient-Sensing Integration
3.1 AMPK
AMPK is activated by increased AMP/ATP ratio. Downstream effects include:
Increased fatty acid oxidation
Increased glucose uptake
Inhibition of mTORC1
Promotion of autophagy
Exercise and caloric restriction activate AMPK across tissues.
3.2 mTOR
mTOR integrates signals from:
Insulin
Amino acids
Cellular energy status
Chronic mTORC1 activation suppresses autophagy and promotes anabolic growth.
In animal models, pharmacologic mTOR inhibition (e.g., rapamycin) extends lifespan.
3.3 Oscillation vs Chronic Activation
Physiological health likely requires dynamic cycling:
Fed state → mTOR activation
Fasted/exertional state → AMPK activation
Modern lifestyles may blunt oscillatory signaling, favoring persistent mTOR dominance.
4. Autophagy and Proteostasis
Autophagy maintains cellular quality control by degrading:
Misfolded proteins
Damaged mitochondria
Protein aggregates
Suppressed autophagy contributes to:
Neurodegeneration
Oncogenesis
Cellular senescence
AMPK promotes autophagy; mTOR inhibits it.
5. Neurodegeneration and Brain Energy Failure
FDG-PET studies show reduced cerebral glucose metabolism decades before clinical Alzheimer’s diagnosis.
Mechanistic overlaps include:
Brain insulin resistance
Mitochondrial dysfunction
Oxidative stress
Reduced NAD⁺ levels
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6. Oncogenic Signaling and Hyperinsulinemia
Insulin and IGF-1 activate PI3K/Akt/mTOR pathways, promoting:
Cell proliferation
Angiogenesis
Reduced apoptosis
Epidemiological data associate hyperinsulinemia with increased risk of colorectal, breast, and pancreatic cancers.
Metabolic modulation strategies are under investigation as adjunctive therapies.
Discussion
This synthesis supports a unifying model:
Chronic nutrient excess → redox imbalance → hyperinsulinemia → persistent mTOR activation → suppressed autophagy → accumulated cellular damage → organ-level disease.
Importantly, this model does not imply singular causation but describes a convergent systems vulnerability.
Interventions that restore metabolic oscillation—exercise, caloric moderation, circadian alignment—appear to normalize redox balance, improve insulin sensitivity, and reactivate autophagic maintenance.
However:
Long-term human data on NAD⁺ supplementation remain limited
Optimal mTOR modulation thresholds are undefined
Disease-specific modifiers (genetics, environment) complicate translation
Limitations
Narrative synthesis, not systematic review
Some mechanistic data derived from animal models
Human RCT evidence limited in duration
Heterogeneity in NAD⁺ precursor formulations
Future Directions
Longitudinal human trials of NAD⁺ modulation
Integrated metabolic biomarker panels (fasting insulin, HOMA-IR, NAD⁺ levels)
Clinical trials combining metabolic interventions with neurodegenerative or oncologic therapies
Genotype-stratified metabolic response studies
Conclusion
Redox balance, insulin signaling, and nutrient sensing form an interconnected regulatory axis governing metabolic resilience.
Persistent disruption of this axis may accelerate aging and increase vulnerability to chronic disease.
Restoration of metabolic flexibility represents a plausible, systems-level strategy for healthspan optimization, though causal hierarchies and therapeutic thresholds require further investigation.
References
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Saxton RA, Sabatini DM. mTOR signaling in growth and disease. Cell. 2017;169:361-371.
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Braidy N, et al. NAD⁺ metabolism in aging and Alzheimer’s disease. Neurosci Biobehav Rev. 2019;98:133-147.
Cunnane S, et al. Brain energy rescue in Alzheimer’s disease. Alzheimers Res Ther. 2016;8:6.
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