Aging: Is the Genome the Clock, or Is Metabolism the Engine?

A new review revives an old biological debate—and reveals why a systems view may be needed.

A bold proposal about the cause of aging

A recent review titled “Causality of Aging Hallmarks” proposes a strikingly simple model of aging.

The authors argue that among the many hallmarks of aging, only one process sits at the top of the causal hierarchy: telomere shortening (and loss of ribosomal DNA repeats).

Their proposed chain of events looks like this:

telomere shortening / rDNA loss

↓

p53 activation

↓

transcriptional reprogramming

↓

aging hallmarks

↓

organismal aging

In this view:

• Telomeres act as a biological clock

• p53 acts as the master signal

• The well-known hallmarks of aging—mitochondrial dysfunction, stem-cell exhaustion, inflammation, and others—are secondary consequences.

It is an elegant and provocative model.

But it also echoes a much older debate in another field of biology.

The same debate already happened in cancer biology

For decades, cancer researchers have debated two competing explanations for the origin of tumors.

The genome hypothesis (dominant model)

The mainstream view in oncology is the somatic mutation theory.

DNA mutations

↓

oncogene activation / tumor suppressor loss

↓

cell signaling changes

↓

metabolic rewiring

↓

cancer

Here, the genome sits at the top of the causal hierarchy.Metabolism is treated mostly as a downstream effect.

The metabolic hypothesis

An alternative view traces back to Otto Warburg.

Warburg observed that cancer cells often rely heavily on glycolysis even when oxygen is available—now known as the Warburg effect.

This led to a different model:

mitochondrial dysfunction

↓

metabolic rewiring

↓

genomic instability

↓

tumor development

In this framework:

• metabolism sits upstream

• genetic changes can emerge as secondary adaptations.

This debate continues today, with researchers increasingly recognizing that both genome and metabolism influence each other.

Aging biology may be facing the same conceptual divide

The telomere-p53 model proposed in the new review resembles the genome-first theory of cancer.

Its logic is clear:

genome damage

↓

p53 signaling

↓

aging hallmarks

Within this model, mitochondria appear mainly as downstream responders to nuclear signals.

Yet many observations in aging biology raise a different possibility.

A metabolic perspective on aging

Across many tissues and diseases, aging is consistently associated with changes in cellular energy metabolism:

• mitochondrial dysfunction

• reduced oxidative capacity

• altered redox balance

• impaired metabolic flexibility.

These changes often appear before major genomic damage becomes evident.

From a metabolic perspective, aging might follow a different sequence:

bioenergetic stress

↓

redox imbalance

↓

cellular stress signaling

↓

DNA damage and senescence

Here, mitochondria are not simply passengers in the aging process.They may act as central regulators of cellular stability.

Why neither view alone fully explains aging

Both perspectives capture important pieces of biology.

The genome clearly matters. Telomere shortening, DNA damage, and p53 signaling all influence aging trajectories.

But metabolism matters as well.

Every cellular process—from DNA repair to protein turnover—requires energy.

Even p53 signaling ultimately depends on the energetic capacity of the cell to execute its programs.

In other words:

signals alone cannot produce biological outcomes

without metabolic execution.

This is where a systems view becomes essential.

A missing layer: bioenergetic capacity

The Exposure-Related Malnutrition (ERM) framework proposes that aging may be strongly influenced by a deeper constraint:

the balance between metabolic demand and mitochondrial oxidative capacity.

In this model, aging emerges when cells face persistent bioenergetic pressure.

environmental exposures + metabolic substrate load + stress signaling

↓

limited mitochondrial throughput

↓

redox imbalance

↓

system-wide adaptation

↓

aging hallmarks

Under these conditions:

• cells shift metabolism

• lipid oxidation declines

• stress pathways activate

• repair processes weaken.

Over time, these pressures can contribute to many recognized hallmarks of aging—including genomic instability, inflammation, and cellular senescence.

Bridging the two perspectives

Rather than choosing between genome-first and metabolism-first explanations, aging biology may need to integrate both.

A simplified systems view might look like this:

environment ↔ metabolism ↔ genome

Where:

• environmental exposures influence metabolism

• metabolism affects genomic stability

• genomic signaling reshapes metabolism

Within this network, mitochondria provide the energetic foundation that allows cellular programs—whether protective or pathological—to be executed.

Why this matters for aging interventions

Different models lead to different strategies.

If aging is primarily driven by telomere shortening, interventions might focus on:

• telomerase activation

• DNA repair mechanisms.

If aging is strongly influenced by metabolic constraints, strategies might emphasize:

• improving mitochondrial function

• restoring metabolic flexibility

• reducing chronic bioenergetic stress.

Most likely, successful approaches will need to address both the genome and the metabolic engine that sustains it.

The bigger lesson

The new review reminds us that aging biology is still searching for its unifying principles.

But it also highlights something deeper.

Across biology—from cancer to aging—the same question keeps returning:

Does life decline because the instructions fail,or because the energy to carry them out runs out?

The answer may lie not in choosing one over the other,but in understanding how information and energy interact across the entire system.

And that is precisely where emerging frameworks like ERM aim to contribute.

Bilu Huang , Xiaowen Hu. Causality of Aging Hallmarks. Aging and disease. 2025 https://doi.org/10.14336/AD.2025.0541