HRT as Geroprotector

A new paper has entered the longevity medicine conversation with unusual ambition and welcome clarity: Perimenopausal Hormone Replacement Treatments as a Geroprotective Approach – Adapting Clinical Guidance. Its central claim is both bold and overdue — that hormone replacement therapy (HRT) should be understood not merely as symptomatic relief, but as a geroprotective intervention capable of influencing the fundamental biology of aging in women.¹

That claim alone represents progress.

For decades, menopause has been framed as a narrow clinical event: a reproductive milestone accompanied by vasomotor symptoms, sleep disruption, mood changes, and genitourinary complaints. Hormone therapy, in turn, has been constrained to the role of palliation — something to be justified, limited, and eventually withdrawn. The new paper challenges that framing by repositioning ovarian endocrine decline as one of the earliest, most systemically consequential accelerators of biological aging.¹

In doing so, it moves menopause medicine decisively closer to geroscience.

But it also reveals — perhaps unintentionally — how incomplete the prevailing medical paradigm remains.

What the Paper Gets Right

The paper’s most important contribution is its systems-level biological framing of menopause. The ovary is not treated as a reproductive afterthought but as a central regulator of whole-body physiology. Estrogen and progesterone receptors are expressed throughout the brain, cardiovascular system, bone, immune cells, skeletal muscle, adipose tissue, and connective tissue. When ovarian hormone production declines, the effects are neither localized nor benign.

The authors map estrogen and progesterone signaling onto all twelve hallmarks of aging, including genomic instability, telomere attrition, epigenetic alterations, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, chronic inflammation, and degradation of the extracellular matrix.² This framing is mechanistically grounded and biologically coherent.

Equally important is the paper’s emphasis on timing. Drawing on cardiovascular, skeletal, metabolic, and neurocognitive data, the authors reinforce what many clinicians observe in practice: initiating HRT during perimenopause or early menopause is biologically distinct from starting it decades later.³ Vascular biology, inflammatory burden, mitochondrial function, and metabolic resilience differ profoundly across these windows.

Taken together, the paper reframes menopause not as a symptomatic inconvenience, but as a critical inflection point in the aging trajectory of women.

A Transitional, Not Yet Transformative, Clinical Position

Despite its forward-looking intent, the paper remains constrained by a transitional clinical mindset. Although the authors clearly move beyond symptom-only prescribing and explicitly endorse early, proactive use of HRT within a healthy longevity framework, hormone therapy is still framed as something to be offered rather than assumed — contingent on individualized justification, extensive risk stratification, and clinician discretion.¹

Biomarkers of aging are thoughtfully catalogued and conceptually elevated, yet largely positioned as emerging tools for future optimization rather than as present-day drivers of initiation and intensity of therapy. Longevity and healthspan extension are embraced as important outcomes, but not yet established as the organizing clinical goal that would fundamentally reorder how endocrine decline in midlife is treated.

In this sense, the paper occupies an important transitional space: it loosens the grip of symptom-based medicine without fully crossing into a physiology-first, longevity-centered paradigm.

The Missing Dimension: Glycobiology and Immune Aging

Nowhere is the incompleteness of the current framework more apparent than in what the paper does not include.

Despite its sophisticated discussion of aging biology, the paper makes no mention of glycans, glycomics, or glycobiology — a striking omission given the extensive literature linking sex hormones, immune aging, and immunoglobulin G (IgG) glycosylation.

This absence matters.

IgG Fc glycosylation is one of the most sensitive integrators of biological aging currently known. The pattern of glycans attached to IgG — particularly levels of galactosylation and sialylation — directly shapes inflammatory tone, Fc receptor engagement, complement activation, and immune effector function. With aging, IgG becomes progressively more agalactosylated and pro-inflammatory, contributing to chronic low-grade inflammation.⁴

Crucially, estradiol is one of the strongest regulators of this process.

Controlled human studies show that suppression of gonadal hormones shifts IgG glycosylation toward a more inflammatory pattern, while estradiol replacement reverses these changes.⁴ Longitudinal studies following women through the menopause transition demonstrate a marked decline in IgG galactosylation and sialylation as estrogen levels fall.⁵ Mechanistic work identifies estrogen-dependent regulation of glycosyltransferases such as ST6GAL1, providing a molecular explanation for these effects.⁶

Even in men, testosterone replacement has been associated with a younger, less inflammatory IgG glycome — an effect that appears largely mediated through aromatization to estradiol.⁷

Taken together, this body of evidence strongly suggests that sex hormone status — and estradiol in particular — plays a central role in immune aging through glycan remodeling. This is precisely the kind of integrative biology one would expect to see in a geroprotective framework, yet it is entirely absent from the paper.

From a longevity-oriented perspective, this omission is not trivial. Glycomics offers a concrete, mechanistically meaningful bridge between endocrine decline, chronic inflammation, immune dysfunction, and biological age — and represents one of the most promising biomarker layers for guiding intervention.

What a Longevity-First Model Demands

A longevity-first approach does not merely ask whether an intervention alleviates symptoms or avoids short-term harm. It asks whether it preserves system-level resilience over time.

From this vantage point, menopause is not simply a stage to be managed; it is a time-limited intervention window during which the trajectory of aging may be meaningfully altered. Hormone replacement, when appropriately timed and formulated, is not an exceptional therapy — it is maintenance of a core regulatory system.

In such a model:

• Symptoms are late indicators, not prerequisites for care

• Biomarkers of aging guide decisions rather than decorate them

• Immune, metabolic, vascular, skeletal, and cognitive aging are treated as interconnected processes

  
  

The paper under discussion moves decisively toward this way of thinking, but it does not fully embrace it. Longevity remains an outcome rather than the organizing principle. Endocrine preservation is suggested rather than assumed.

An Important Bridge — Not the Destination

This paper deserves recognition. It reconnects ovarian aging to systemic decline. It challenges outdated fears surrounding hormone therapy. It introduces geroscience concepts into menopause medicine with rigor and restraint.

But it remains a bridge between paradigms rather than the paradigm itself.

A more complete shift requires medicine to move beyond reacting to disease and toward preserving physiology before irreversible decline. It requires integrating endocrine biology, immune aging, glycan remodeling, and system-level biomarkers into a coherent strategy aimed at extending healthspan.

Viewed through that lens, menopause is not simply the end of reproduction.

It is an inflection point — and one that medicine has only just begun to understand.

Notes & References

1. Rabinovici J, Oonk H-P, Huang Z, et al. Perimenopausal Hormone Replacement Treatments as a Geroprotective Approach – Adapting Clinical Guidance. Aging and Disease. 2026.

2. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: An expanding universe. Cell. 2023.

3. Hodis HN, Mack WJ. Hormone replacement therapy and the timing hypothesis. J Steroid Biochem Mol Biol. 2014.

4. Ercan A, Kohrt WM, Cui J, et al. Estrogens regulate glycosylation of IgG in women and men. JCI Insight. 2017.

5. Deriš H, Kifer D, Cindrić A, et al. Immunoglobulin G glycome composition in transition from premenopause to postmenopause. iScience. 2022.

6. Scherer HU, Häupl T, Burmester G-R, et al. Estrogen induces ST6GAL1 expression and increases IgG sialylation. Arthritis Research & Therapy. 2018.

7. Subramanian S, et al. Effects of testosterone and metformin on the GlycanAge index of biological age. GeroScience. 2024.