17α-Estradiol: A Novel Therapeutic Intervention to Target Age-related Chronic Inflammation

Aging is a biological process characterized by a gradual and multifactorial decline in physiological function. This decline is accompanied by a chronic, low-grade inflammation (referred to as “inflammaging”), which leads to an accumulation of molecular and cellular damage that ultimately increases morbidity and mortality in elderly people (1,2). This chronic inflammatory process affects more male than female individuals and is also involved in early onset of age-related diseases including sarcopenia, neurodegeneration, and metabolic diseases (3). In addition, age-associated attenuation of sex hormones may also be responsible for triggering muscle weakness and atrophy, decreased functional performance, and changes in metabolic/energy homeostasis and lipid distribution (4,5). The steroid sex hormone 17-beta estradiol (17β-E2) has potent estrogenic properties, whereas 17-alpha estradiol (17α-E2) is considered a nonfeminizing estrogen with reduced affinity for the estrogen receptor. Interestingly, it has been hypothesized that 17α-E2 could be as effective as 17β-E2 in the protection against oxidative stress, amyloid toxicity, and Parkinson’s and Alzheimer’s diseases (6). 17α-E2 is the predominant form of estradiol in mouse and rat brains (7) and is considered a good candidate for testing its neuroprotective potential when given to humans (8). Treatment with 17α-E2 reduces body weight while extending life span in male mice (9,10); however, the physiological mechanisms underlying these effects remain unclear. In this edition of The Journals of Gerontology, Series A: Biological Sciences and Medical Sciences, Stout and colleagues (11) test whether late life administration of 17α-E2 could mitigate age-related metabolic dysfunction and inflammation in male mice C75BL/6, thereby positively affecting health span. Two dietary interventions with 17α-E2 were carried; in the first experiment, 17α-E2 was given to 18-month-old mice for 15 weeks, whereas a 5-week treatment with 17α-E2 was performed in 20-month-old mice for the second study. In the latest study, a group of mice on calorie restriction was included. Physiological parameters such as body mass, body composition, body temperature, food intake, and fasting glucose were measured daily or weekly depending on the study. Brain, white adipose tissue (WAT), liver, and quadriceps were collected for different analyses. The main finding in the study is that treatment with 17α-E2 reduces body mass and adiposity, likely through a reduction in calorie intake. The authors propose that activation of the hypothalamic leptin signaling pathway rather than a remodeling in the metabolic balance, a well-known hallmark of calorie restriction (12,13), could be at play. Consistent with these observations, energy expenditure and energy content in feces were not altered between experimental groups. Decreased plasma and epididymal WAT levels of proinflammatory markers, such as tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), were observed after 17α-E2 treatment together with the suppression of a senescence-associated secretory phenotype in WAT. However, this attenuation was not accompanied by a reduction in the number of senescent cells in WAT. Finally, the authors report the lack of deleterious effects of 17α-E2, such as feminization and impairment in cardiac and physical functions, confirming its weak estrogenic potential male mice. In summary, Stout and colleagues elegantly demonstrate that 17α-E2 intervention in mid-life and in old mice mitigates age-associated metabolic and inflammatory disfunctions through calorie intake reduction and adjustment of the nutrient-sensing signaling pathway in visceral adipose tissue. By reversing the age-related lipid redistribution, 17α-E2 may, therefore, improve liver function and glucose homeostasis. The observations presented in this study support the notion that 17α-E2 supplementation confers metabolic benefits comparable with the effects of chronic calorie restriction and other forms of dietary restriction (14,15). There is a need to identify the specific molecular and cellular mechanisms of action of 17α-E2 in order to develop novel interventions able to delay the aging process. Further understanding of the modulation of leptin signaling by 17α-E2 could open new avenues to treat age-related metabolic diseases, including obesity, which is considered one of the two major epidemics of the 21st century (16).