Beyond Hormones: Completing the Geroprotection Puzzle in Women’s Aging

For decades, hormone replacement therapy (HRT) has been framed narrowly—as a way to relieve hot flashes, improve sleep, or manage menopausal symptoms. A recent Perspective published in Aging and Disease challenges this limited view, arguing that perimenopausal HRT should be reconsidered as a potential geroprotective intervention, capable of influencing long-term healthspan rather than just short-term comfort.

This is an important and timely reframing. But to fully realize its promise, one more piece of biology needs to be brought clearly into focus.

What the Perspective Gets Right

The authors make several strong points:

• Ovarian aging is an early driver of systemic aging, not just a reproductive milestone.

• The perimenopausal transition is a critical window during which intervention may meaningfully alter trajectories of cardiovascular, metabolic, musculoskeletal, and cognitive aging.

• Estrogen and progesterone influence multiple hallmarks of aging, including inflammation, mitochondrial function, proteostasis, and cellular senescence.

• When started early and appropriately tailored, HRT is associated with improvements in quality of life and reductions in downstream disease risk.

• Future care should move toward biomarker-guided, personalized longevity medicine, rather than symptom-based prescribing alone.

Together, these arguments support a paradigm shift: women’s aging biology deserves proactive, mechanistically informed care—not reactive symptom management.

The Missing Layer: Command vs. Execution

Where this conversation often becomes incomplete is in how hormonal signals are interpreted biologically.

Sex hormones such as estrogen and progesterone function primarily as regulatory command signals. They coordinate gene expression, receptor sensitivity, immune tone, and metabolic priorities. In other words, they help decide what the body should do.

But they are not the primary executors of repair, recovery, or resilience.

That role belongs largely to mitochondria and bioenergetic systems.

Every putative geroprotective benefit of HRT—whether improved bone remodeling, vascular repair, neuroplasticity, or metabolic flexibility—ultimately requires:

• Adequate mitochondrial capacity

• Sufficient ATP production

• Redox balance

• Access to metabolic substrates

Without these, hormonal instructions may be well-phrased—but poorly carried out.

Why This Matters Clinically

This distinction helps explain a reality clinicians see every day:

• Some women experience profound benefits from HRT

• Others report modest or inconsistent effects

• A subset feels worse, despite “optimal” hormone levels

This variability is often attributed to dosing, formulation, or receptor differences. But a deeper explanation is likely bioenergetic readiness.

If mitochondrial systems are constrained by chronic stress, inflammation, undernutrition, toxic exposures, or long-standing metabolic adaptation, then restoring hormonal signaling alone may:

• Produce a limited benefit

• Fail to trigger recovery

• Or even increase physiological strain by raising energetic demand without execution capacity

This is not a failure of hormones—it is a mismatch between signals and resources.

How ERM Completes the Picture

The framework of Exposure-Related Malnutrition (ERM) helps integrate these layers.

ERM describes a state in which chronic exposures—psychological stress, inflammatory load, metabolic dysregulation, environmental toxins, sleep disruption—drive long-term bioenergetic compromise. The body adapts by reallocating limited energy toward short-term survival at the expense of repair, recovery, and resilience.

In this context:

• HRT can help restore clearer endocrine signaling

• But recovery depends on whether mitochondrial systems can execute those signals

• True geroprotection requires addressing both sides: command and execution

When HRT is paired with strategies that restore mitochondrial throughput—through improved nutrient availability, metabolic rhythm, inflammation resolution, sleep, and recovery biology—the conditions for healthspan extension become far more realistic.

Toward a More Complete Model of Women’s Longevity

The Aging and Disease perspective takes an important step by repositioning HRT within geroscience. The next step is to embed endocrine therapy within a bioenergetic framework that acknowledges limits, trade-offs, and heterogeneity.

In this more complete model:

• Hormones set direction

• Mitochondria determine feasibility

• Healthspan emerges from the alignment between the two

Women are not “broken” at midlife. Often, they are exhausted at the cellular level—and no signal, however elegant, can substitute for the energy required to heal.

If we are serious about healthy longevity, we must move beyond single-layer solutions and toward systems-level care that respects both biology and bioenergetics.

That is where the real opportunity lies.

Rabinovici, J., Oonk, H.-P., Huang, Z., Mirando, T., Zhou, M., Strauss, T., Olari, L.-R., Wilczok, D., Maier, A. B., & Bischof, E. (2027). Perimenopausal hormone replacement treatments as a geroprotective approach: Adapting clinical guidance. Aging and Disease, 18(2). https://doi.org/10.14336/AD.2025.1391