Why Aging Is Not a Signaling Problem: Insights from Geroscience and Mitochondrial Recovery

In a recent geroscience review, Nicoletti et al. (2025) synthesize decades of research on the core nutrient- and stress-sensing pathways that dominate modern aging biology—mTOR, AMPK, sirtuins, IGF-1/GH, and NAD⁺ metabolism. Their message is both familiar and important: aging is shaped by conserved biological programs that continuously sense energy availability, stress, and growth signals, and then recalibrate physiology accordingly.

But when this review is viewed through a Respond → Adapt → Recover framework, an important clarification emerges—one that helps explain why so many “longevity pathways” look promising on paper yet deliver modest results in real people.

Respond and Adapt: The Biology We Understand Well

Nicoletti’s review excels at describing the Respond and Adapt phases of stress biology.

• Respond: Pathways like AMPK and mTOR rapidly sense energetic stress or nutrient abundance.

• Adapt: These same pathways suppress growth, promote catabolism, activate stress resistance, and shift resources toward short-term survival.

This is not dysfunction. It is evolutionarily conserved intelligence.When energy is scarce or stress is persistent, suppressing growth and prioritizing survival is exactly what biology should do.

From this perspective, many features associated with aging—lower IGF-1 signaling, chronic AMPK activation, reduced mTOR activity—are not “broken.” They are adaptive decisions.

Nicoletti et al. are absolutely right to emphasize this.

Where the Gap Appears: Recovery Is Not Automatic

What the review touches only indirectly—and what becomes clear in a Respond–Adapt–Recover framework—is that successful adaptation does not guarantee successful recovery.

Most aging and longevity discussions implicitly assume that once stress subsides or pathways are modulated, the system will naturally rebound. But biologically, recovery is not passive.

Recovery is an active, ATP-intensive phase that requires:

• Adequate mitochondrial reserve capacity

• Efficient redox balance

• Continuous NAD⁺ regeneration

• Time and substrate availability for repair and re-anabolism

This is where many interventions fail—not because signaling is wrong, but because execution is constrained.

Mitochondria: The Executors, Not the Messengers

Nicoletti’s review catalogs the decision layers of aging biology. The Respond–Adapt–Recover framework adds a crucial distinction:

Signaling decides. Mitochondria execute.

mTOR, AMPK, sirtuins, and IGF-1/GH can correctly signal “now is the time to repair.”But if mitochondria cannot deliver sufficient ATP, redox flexibility, and NAD⁺ flux, repair simply does not happen.

This explains a paradox many clinicians and patients recognize:

• Hormones look “normal”

• Pathways appear appropriately activated

• Yet fatigue, poor recovery, inflammation, and functional decline persist

The bottleneck is not awareness—it is bioenergetic capacity.

Aging Reframed: From Damage to Failed Resolution

Seen this way, aging is not just the accumulation of molecular damage, nor simply misregulated pathways. It is increasingly a story of repeated recovery failure.

• Stress responses can persist under energetic constraint because they are largely catabolic.

• Repair and regeneration fail first because they are anabolic and energy-demanding.

Nicoletti’s review helps us understand how the system adapts.

The Respond–Adapt–Recover lens explains why adaptation so often becomes chronic.

Why This Matters Clinically

This distinction has real consequences for aging interventions:

• Downstream pathway modulation (anti-inflammatory drugs, hormonal tweaks, mTOR inhibitors) may reduce load or symptoms—but often does not restore resilience.

• Mitochondrial-centered strategies—those that improve substrate handling, redox balance, reserve capacity, and NAD⁺ regeneration—are more likely to restore the ability to recover across systems.

In other words, longevity is not achieved by pushing the right molecular buttons alone. It requires funding recovery at the level where biology actually does the work.

The Take-Home Message

Nicoletti et al. provide a strong, coherent map of aging’s regulatory architecture. When integrated with a Respond–Adapt–Recover framework, their work points to a deeper conclusion:

Aging is not primarily a failure of sensing or signaling. It is a failure of bioenergetic execution.

Mitochondria sit at the center of this story—not as passive power plants, but as the rate-limiting infrastructure of recovery. Until aging science fully accounts for this execution bottleneck, even the most elegant signaling models will struggle to translate into durable improvements in healthspan.

Understanding this shift—from regulation to execution—may be one of the most important steps forward in aging science.

Nicoletti, G. R. P., Mangano, K., Nicoletti, F., & Cavalli, E. (2025). From Elixirs to Geroscience: A Historical and Molecular Perspective on Anti-Aging Medicine. Molecules, 30(24), 4728. https://doi.org/10.3390/molecules30244728