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

Abstract

Like humans, rhesus macaques (Macaca mulatta) are large, long-lived diurnal primates, and show similar age-related changes in the secretion of many steroid hormones, including oestradiol, testosterone, cortisol, and dehydroepiandrosterone (DHEA). Consequently, they represent a pragmatic animal model in which to examine the mechanisms by which these steroidal changes contribute to perturbed sleep-wake cycles and cognitive decline in the elderly. Using remote serial blood sampling we have found the circulating levels of DHEA sulphate, as well as oestradiol and testosterone, decline markedly in old monkeys. Furthermore, using real-time PCR, we have shown that genes associated with the conversion of DHEA to oestradiol and testosterone (e.g., 3BHSD, 17BHSD, and aromatase) are highly expressed in brain areas associated with cognition and behavior, including the hippocampus, prefrontal cortex, and amygdala. Taken together, these findings suggest that administration of supplementary DHEA in the elderly may have therapeutic potential for cognitive and behavioral disorders, but with fewer negative side effects outside of the central nervous system. To test this we have developed a novel steroid supplementation paradigm for use in old animals; this involves oral administration of DHEA and testosterone at physiologically relevant times of the day to mimic the circadian hormone patterns observed in young adults. We are currently evaluating the efficacy of this steroid supplementation paradigm at reversing age-associated disorders, including perturbed sleep-wake cycles and cognitive decline as well as impaired immune response.

Short-term testosterone manipulations do not affect cognition or motor function but differentially modulate emotions in young and older male rhesus monkeys

“…They exhibit age-related declines in cognition (Baxter, 2001; Herndon and Lacreuse, 2002; Herndon et al, 1997), fine motor function (Lacreuse et al, 2005; Zhang et al, 2000), and T levels (Sorwell and Urbanski, 2013) that closely resemble those observed in humans. In addition, rhesus monkeys are highly social primates that share a vast repertoire of socioemotional behaviors with humans (Kalin and Shelton, 2003).…”

“…Second, baseline T levels were based on 4 weekly blood samples which were collected in the morning. Given that T shows a clear circadian rhythm and is released in a pulsatile manner (Sitzmann et al, 2014), serial blood samples may be necessary to accurately capture age-related differences in T levels in male rhesus monkeys (Sorwell and Urbanski, 2013; Urbanski and Sorwell, 2012). …”

“…Male rhesus monkeys are particularly well suited for investigating the effects of T on cognition, motor function and emotions because they share many characteristics with humans, including in the organization of the brain and neuroendocrine systems (Sorwell and Urbanski, 2013). They exhibit age-related declines in cognition (Baxter, 2001; Herndon and Lacreuse, 2002; Herndon et al, 1997), fine motor function (Lacreuse et al, 2005; Zhang et al, 2000), and T levels (Sorwell and Urbanski, 2013) that closely resemble those observed in humans.…”

Neurocognitive effects of estrogens across the adult lifespan in nonhuman primates: State of knowledge and new perspectives

“…There are fewer limitations with NHP. Macaques are excellent models for studies on sleep (Sorwell and Urbanski, 2013;Zhdanova et al, 2011) and its impact on cognition (Haley et al, 2009). They have also been used as models for hot flashes, in two small studies that remain to date the only published studies on this topic in NHP (Dierschke et al, 1985;Jelinek et al, 1984).…”

“…Macaques, in particular Macaca mulatta (rhesus monkey) and M. fascicularis (cynomolgus monkey) have been the NHP models of choice to study the neurocognitive effects of estrogens (Lacreuse, 2006;Voytko et al, 2009b), due to their ubiquity as laboratory animals and close similarities with humans in the organization and function of the brain (Capitanio and Emborg, 2008;Roelfsema and Treue, 2014) and the Hypothalamic-PituitaryGonadal axis (Knobil and Hotchkiss, 1988;Sorwell and Urbanski, 2013). Only a handful of studies have been conducted in other Old World monkeys and they will be mentioned as necessary.…”