Beyond their use for conditions of severe hormone deficiency, hormone therapies are one of the higher profile approaches taken by the less rigorous, more dubious end of the “anti-aging” medical community. An interesting consequence of the greater focus on underlying mechanisms of aging in the research and development community, particularly senescent cell accumulation at the present time, is that scientists and physicians now have access to a novel set of measurements that are definitively connected to aging, and can use those measurements to try to figure out whether any of the overhyped, dubious strategies in the “anti-aging” marketplace are actually doing something useful (even if marginal) under the hood.

Senescent cells secrete a potent mix of inflammatory and other molecules, the senescence-associated secretory phenotype (SASP). This is how a comparatively small number of lingering senescent cells in aged tissues cause harm: their signaling disrupts tissue structure and maintenance, and produces a state of chronic inflammation that drives the onset and progression of many age-related conditions. Over the past few years, the SASP has been far more extensively mapped than was previously the case. Measuring circulating levels of the more prominent SASP molecules is a way to assess the burden of aging, or at least that due to this particular aspect of age.

That is the approach taken in today’s open access paper, in which the authors report that hormone treatment of postmenopausal women is associated with lower levels of some of the SASP factors known to be involved in inflammatory signaling. Whether this reflects a lesser burden of senescent cells, or a reduced signaling of such cells is an open question, though the authors here seem to lean towards the latter possibility, given what is known of the way which estrogen regulates metabolism. In general, hormones have extremely broad effects on metabolism, and it is certainly the case that their use comes with many caveats.

Effect of menopausal hormone therapy on proteins associated with senescence and inflammation

Cell senescence, a state of cell cycle arrest due to the finite capacity of cells to proliferate, also occurs as a result of the accumulation of molecular and cellular damage. Senescent cells secrete an array of cytokines, chemokines, growth factors, and proteases collectively referred to as the senescence-associated secretory phenotype (SASP). The array of SASP proteins includes many proteins that have been shown to be regulated by estrogen and to be secreted by platelets, leukocytes, and vascular endothelium including the metalloproteins (MMPs), tumor necrosis factor-α (TNF-α), ecosinoids, and serotonin. However, other proteins considered to be part of the SASP array (e.g., GDF15, Fas, MIP1α, and TNFR1) may be more specific indicators of the systemic senescent cell burden.

In response to DNA damage, senescence serves as an anticancer mechanism and may also have beneficial functions in embryogenesis, parturition, and tissue repair. However, senescent cells that are not cleared efficiently by the immune system disrupt tissue function, which increases the vulnerability to the onset and progression of a host of age-related diseases, including pulmonary dysfunction, cardiovascular disorders, osteoporosis, neurodegeneration, and diabetes. In part, the deleterious effects of senescent cells are mediated by the SASP. Strategies to remove senescent cells and suppress the SASP are now being pursued as a means to counter age-related diseases and geriatric syndromes.

Estrogen is a steroid hormone implicated in modulating cell senescence. For example, estrogen decreases cell senescence in endothelial progenitor cells, and activates estrogen receptor alpha (ERα) to inhibit cell senescence-like phenotypes in human epithelial cells. Estrogen also slows deficits associated with aging and cell senescence in bone, such as declining bone density. However, little is known regarding how cell senescence might be modified by natural changes in hormone concentrations, such as those that occur during menopause, and how this might be modulated by hormone therapies. This study examined whether menopausal hormone therapies, in the form of oral conjugated equine estrogens (oCEE) and transdermal 17β-estradiol (tE2), altered the circulating levels of a specific set of SASP proteins in women who had undergone natural menopause.

Growth differentiation factor 15 (GDF15), tumor necrosis factor receptor 1 (TNFR1), FAS, and macrophage inflammatory protein 1α (MIP1α) were measured in serum. Results were compared among menopausal women participating in the Kronos Early Estrogen Prevention Study randomized to either placebo (n = 38), oral conjugated equine estrogen (oCEE, n = 37), or transdermal 17β-estradiol (tE2, n = 34). Serum levels of the senescent markers for each treatment were compared to placebo 36 months after randomization. We found that serum levels of GDF15, TNFR1, and FAS, but not MIP1α, were lower in both the oCEE and tE2 groups compared to placebo. Differences in the magnitude of effect of the two active treatments may reflect the differences in circulating levels of estrogen metabolites due to formulation and mode of delivery.