We’ve had this discussion before in another thread and taking 17a-estradiol or doing exercise achieves the same or better longevity results as castration. There is also frailty to consider.
Does finasteride extend lifespan? Is it DHT or testosterone that makes male lifespan shorter than female? (Or neither —both) It is embarrassing how much we don’t know at this late date.
As 17aE2 is a 5 alpha reductase inhibitor (Schriefers et al., 1991), one such mechanism might involve inhibition of testosterone’s conversion to dihydrotestosterone, which is a more potent binder of the AR. This could inhibit specific effects of testosterone on metabolism, which include protein anabolism and inhibition of urea cycling (Lam et al., 2017; Rossetti, Steiner & Gordon, 2017), and contribute to the observed elevation of amino acids and urea cycling. Under this hypothesis, inhibition AR expression in mice would be expected to inhibit 17aE2 responses, and other 5-alpha reductase inhibitors might induce similar effects to 17aE2.
Another related hypothesis is that the activity, metabolism and/or signaling effects of 17aE2 are dependent on testosterone, and without the presence of testosterone the biological effects of 17aE2 are weaker. Two of the liver metabolites that showed strong, sex-specific responses to 17aE2 were the estrogenic compounds estriol-3-sulfate and 16-oxoestradiol 3-sulfate—products that can be generated from metabolism of estradiol. Estriol is produced from the placenta during pregnancy in females and during nonpregnant states is generated from estradiol or estrone via 16-alpha hydroxylation (Longcope 1984).
With 5ar inhibition at least, the causal pathway for how it extends lifespan in male mice could be reduction of prostate cancer death rates which likely make up a significant portion of all deaths in male mice (since mice primarily die of cancer).
Sounds plausible as it seems consistent with the antagonistic pleiotrophy model. The hormones and other factors that contribute to fecundity and growth may be harmful in old age.
My N=1 experience: had a healthy pregnancy and healthy baby at age 34, but shortly after had two miscarriages, and then very early menopause. So my fecundity was short lived. (I realized that I had probably had my child at the last possible moment). Will never know for certain whether there was something “wrong” with me or whether my early fertility shutdown was just another expression of my overall low-growth, catabolic-leaning phenotype.
