Hormone Supplementation During Aging: How Much and When?

Abstract

Circulating levels of dehydroepiandrosterone, a major adrenal steroid, show a marked age-related decrease in both humans and nonhuman primates. Because this decrease has been implicated in age-related cognitive decline, we administered supplementary dehydroepiandrosterone to perimenopausal rhesus macaques (Macaca mulatta) to test for cognitive benefits. Although recognition memory improved, there was no benefit to spatial working memory. To address the limitations of this study we developed a hormone supplementation regimen in aged male macaques that more accurately replicates the 24-hr androgen profiles of young animals. We hypothesize that this more comprehensive physiological hormone replacement paradigm will enhance cognitive function in the elderly.

Causes and Consequences of Age‐Related Steroid Hormone Changes: Insights Gained from Nonhuman Primates

“…The animals were tested when they were on and off treatment, allowing for a within‐subjects examination of the effect of DHEA. Despite promising evidence from rodent studies that DHEA improves cognitive performance , we saw no improvement of performance in a delayed match‐to‐sample test or a spatial delayed response task . Although the lack of an effect is discouraging, it does contribute to the validation of the aged macaque as a model for human ageing because the finding is consistent with the plethora of clinical studies that have failed to observe cognitive benefit of DHEA supplementation in aged men or women .…”

“…It is also possible that existing hormone supplementation paradigms do not adequately mimic the endogenous circadian hormone profiles and so are less effective, or even detrimental. To explore this possibility, we have recently initiated a study involving old male rhesus macaques, in which we are assessing the efficacy of androgen supplementation on a wide range of physiological functions, including sleep–wake cycles, cognition and immune function . What makes this study especially pertinent is that the daily combined testosterone–DHEA supplementation paradigm not only raises mean circulating levels of DHEAS, testosterone, dihydrotestosterone (DHT) and oestradiol to juvenile levels, but also preserves the normal 24‐h pattern of these hormones in the circulation (Fig.…”

The Rhesus Macaque as a Translational Model for Neurodegeneration and Alzheimer’s Disease

“…The first two phenotypes are seen in very old monkeys, but progression to tombstone cells is uncommon. the clinic (Rapp, 1989;Peters et al, 1996;Moore et al, 2006;Nagahara et al, 2010) and also shows similar life stages; i.e., a prolonged childhood, adolescence, adulthood, and cognitive and hormonal aging declines (Downs and Urbanski, 2006;Messaoudi et al, 2011;Sorwell et al, 2012;Mattison et al, 2017). For these reasons, the rhesus macaque may represent a more holistic and systems approach to studying mechanisms underlying human aging.…”

Testosterone Increases Circulating Dehydroepiandrosterone Sulfate Levels in the Male Rhesus Macaque

“…We used the rhesus macaque, a large diurnal primate with endocrine physiology very similar to that of humans, to investigate the interactions between DHEA/S and testosterone. Because we recently observed novel interactions in a combined androgen supplementation paradigm ( 12 , 13 ), we have expanded on this previous research to formulate a working hypothesis for adrenal and gonadal interactions. Our results indicate a strong influence of testosterone on circulating levels of DHEAS, possibly explaining the drastic differences between male and female levels of the hormone.…”