Aging, Regeneration, and the Missing Rhythm: When Models Jump Too Quickly to Intervention

In recent years, aging science has moved decisively away from the idea of aging as a fixed, irreversible decline. Instead, many contemporary models frame aging as a dynamic, potentially modifiable process shaped by stress, repair, and recovery capacity. Among these, a recent review proposing a “regeneration model of aging” adds another thoughtful voice to the conversation.

The core proposal is appealing: aging reflects a failure of regeneration rather than the inevitable accumulation of damage. In this model, cellular stress leads to DNA damage, inflammation, and senescence, while successful resolution—mediated largely through AMPK signaling—supports repair, resilience, and extended healthspan.

This perspective aligns with a broader shift in geroscience. However, when placed alongside other established aging frameworks, important conceptual gaps become visible—particularly around time, rhythm, and recovery execution.

Many Models of Aging, One Shared Challenge

Modern aging models include:

• Damage accumulation (DNA damage, oxidative stress)

• Hallmarks of aging (genomic instability, mitochondrial dysfunction, senescence)

• Hyperfunction models (mTOR-driven growth beyond usefulness)

• Hormesis and stress-adaptation models

• Mitochondrial allostatic load

• Inflammaging and immune remodeling

The regeneration model fits naturally within this ecosystem by emphasizing repair capacity rather than damage alone. Where it is strongest is in highlighting AMPK as a central integrator of energy stress, DNA repair, autophagy, and immune resolution.

But this is also where the model begins to overreach.

The Fundamental Concept Missing: Regeneration Is a Cycle, Not a Switch

A central limitation of the regeneration model is that it treats AMPK activation as both the signal and the solution.

Biologically, AMPK governs:

• Stress sensing

• Energy triage

• Autophagy

• Survival during scarcity

These processes are essential—but they are not regenerative on their own.

True regeneration requires a completed cycle:

1. Stress response (often AMPK-dominant)

2. Damage containment and cleanup

3. Resolution of stress

4. Transition to anabolic rebuilding

5. Restoration of tissue structure and function

That fourth step—anabolic recovery, largely dependent on mTOR signaling and substrate availability—is largely absent from the model.

Without it:

• Repair becomes net loss

• Autophagy erodes tissue mass

• Satellite cells stall

• Immune systems quiet but do not rebuild

• Healthspan may decline despite “healthy signaling”

In short, cleanup is not regeneration.

Rhythm Matters More Than Activation

Another missing element is tempo.

Biological systems do not benefit from sustained activation of stress pathways, even protective ones. Chronic AMPK dominance—whether driven by illness, undernutrition, excessive fasting, overtraining, or psychological stress—can lead to:

• Sarcopenia

• Immune suppression

• Fertility impairment

• Frailty

• Poor recovery despite “good habits”

Healthy aging depends not on how much AMPK is activated, but on when, for how long, and whether the system can exit that state.

This anabolic–catabolic rhythm—AMPK followed by mTOR—is foundational biology, not a downstream detail.

A Premature Leap to Intervention

One of the more concerning aspects of the model is how quickly it moves from concept to prescription.

The review’s figures suggest that activating AMPK through lifestyle or pharmacologic means can directly restore healthspan, implicitly positioning AMPK as a therapeutic endpoint. This is premature.

Before intervention, a model must answer:

• What defines successful recovery?

• When should AMPK activation stop?

• What enables rebuilding?

• How does substrate availability constrain outcomes?

• What happens in systems already energy-depleted?

Without these answers, well-intended interventions risk locking people into survival mode, especially those already living with chronic stress or illness.

Where the ERM Framework Completes the Picture

The Exposure-Related Malnutrition (ERM) framework addresses precisely these gaps.

ERM reframes aging and chronic disease not as signaling failures, but as failures of bioenergetic execution under persistent stress. It distinguishes:

• Signals vs. capacity

• Repair vs. recovery

• Activation vs. resolution

• Adaptation vs. exhaustion

In ERM:

• AMPK activation is expected—and often excessive

• The problem is insufficient energy, substrates, or timing to complete recovery

• Health declines not because repair is absent, but because rebuilding is impossible

This explains why many people “do everything right” and still deteriorate—and why generic longevity advice often fails in real-world patients.

The Takeaway

The regeneration model of aging is a valuable contribution. It reinforces the idea that aging is not fixed, and that recovery capacity matters.

But regeneration is not achieved by activating stress-response pathways alone.

Without rhythm, sequencing, and bioenergetic sufficiency, repair resolves into loss—not renewal.

Before we rush to intervention, we must finish the conceptual work. Aging is not a switch to be flipped, but a cycle that must be completed.

And in that cycle, recovery—not just repair—is the missing step.

Dassoff, E. The regeneration model of aging and its practical implications. Discov Med 3, 3 (2026). https://doi.org/10.1007/s44337-025-00558-5