Exp Gerontol. 2011 Feb-Mar;46(2-3):100-7. Epub 2010 Sep 17.The reproductive-cell cycle theory of aging: an update.Atwood CS, Bowen RL.
This is a recent paper by Bowen RL and it lays out an interesting theory. My original interpretation of antagonistic pleiotropy with regard to reproductive hormones was that the end-product, testosterone and estrogen (plus others) were the main effectors however this paper brings into light the entire hypothalamic pituitary gonadal axis (HPG). In summary the author's propose that because the feedback hormones to the HPG axis, for e.g. testosterone and inhibin, is low LH is produced in excess however due to senescence the cells can't respond leading to endocrine dyscrasia. It is not the lack of testosterone but the increase in LH leading to the effects of aging.
With regards to testosterone there has been fear that supplementation will place men at risk for various chronic diseases, however Bowen claims:
Unfortunately, experimental evidence from hormone replacement therapy studies has been confounded by the use of non-physiologically and non-biochemically relevant hormone replacement therapies.
The paper goes on to describe and explain this theory in regards to CVD, CVA, osteoporosis, AD, etc... For example their mechanistic explanation for osteoporosis:
Mechanistic evidence for FSH as mediating bone loss comes from studies indicating that FSH increases osteoclastogenesis and bone resorption, and from in vivo studies indicating that despite having E2 deficiency, FSH-receptor-null mice have normal bone mass ( [Sun et al., 2006] and [Wu et al., 2007] ). Further, in vivo studies indicate that FSHβ mutant mice (~ 50% reduction in circulating FSH) display a high bone mass despite being eugonadal, due to reduced bone resorption (Sun et al., 2006). Similarly, hypogonadal FSHβ−/− mice also fail to lose bone despite severe hypogonadism. Moreover, aromatase−/− mice, a model for chronic hypogonadism, display a doubling of resorption surfaces in the presence of high FSH, whereas ERα−/−β−/− or GnRHmuthpg mice, in which estrogen deficiency is as severe but is not accompanied by high FSH levels, do not show the expected increases in bone resorption ( [Miyaura et al., 2001] and [Sims et al., 2002] ). Effects of E2 on bone metabolism are also clearly important perhaps as an antiresorptive agent; deletion of ERα in osteoclasts result in bone loss and increased resorption in the face of normal FSH levels (Nakamura et al., 2007), while GnRH agonists cause high turnover bone loss despite reduced FSH levels (Sanyal et al., 2008 A. Sanyal, K.A. Hoey, U.I. Modder, J.L. Lamsam, L.K. McCready, J.M. Peterson, S.J. Achenbach, M.J. Oursler and S. Khosla, Regulation of bone turnover by sex steroids in men. J. Bone Miner. Res., 23 (2008), pp. 705–714. | View Record in Scopus | | Cited By in Scopus (10)Sanyal et al., 2008). Together these data indicate that the ratio of FSH to E2 may dictate bone resorption, with an increase in the ratio promoting bone resorption. These data also suggest a potential role for GnRH signaling. Evidence also exists for inhibins A and B, which decline following menopause in women and with aging in men, as regulating bone metabolism.
This may be compelling support for physiological levels of HRT with inhibin. Calorie restriction doesn't only decrease things like testosterone, as I understand it it suppresses the entire HPG axis. The author's propose either HRT w/ inhibin, or GnRH agonists/antagonists (the agonists work because of sensitization of the receptors leading to downregulation). However for those supplementing with nonphysiological versions of hormones and also without inhibin, you may be aging faster then without it.
References
01. Mayo Clin Proc. 2007 Jan;82(1):29-39.Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of randomized placebo-controlled trials.Haddad RM, Kennedy CC, Caples SM, Tracz MJ, Boloña ER, Sideras K, Uraga MV, Erwin PJ, Montori VM.
