A rapidly aging population in Korea has led to increased attention in the field of anti-aging medicine. The purpose of anti-aging medicine is to slow, stop, or reverse the aging process and its associated effects, such as disability and frailty. Anti-aging medicine is emerging as a growing industry, but many supplements or protocols are available that do not have scientific evidence to support their claims. In this review, the mechanisms of action and the clinical implications of anti-aging interventions were examined and explained. Calorie restriction mimetics define compounds that imitate the outcome of calorie restriction, including an activator of AMP protein kinase (metformin), inhibitor of growth hormone/insulin-like growth factor-1 axis (pegvisomant), inhibitor of mammalian target of rapamycin (rapamycin), and activator of the sirtuin pathway (resveratrol). Hormonal replacement has also been widely used in the elderly population to improve their quality of life. Manipulating healthy gut microbiota through prebiotic/probiotics or fecal microbiota transplantation has significant potential in anti-aging medicine. Vitamin D is expected to be a primary anti-aging medicine in the near future due to its numerous positive effects in the elderly population.
HORMONAL REPLACEMENT
Hormone levels decrease with age, and this process is related to decreased secretion from the pituitary gland, adrenals, and gonads [43]. Decreased hormone levels are associated with decreases in bone mineral density (BMD), muscle mass, sexual desire, erectile function, and intellectual activity. In this context, hormone supplements have been widely used to help reverse the effects of aging and improve the quality of life in the elderly.
1. Estrogen and Progestins
Two-thirds of women suffer from uncomfortable symptoms like hot flashes or vaginal dryness during perimenopause, and HRT is used to reduce such symptoms. Estrogens alone, or together with progester one, have positive effects on osteoporosis treatment and have been used to prevent vertebral and non-vertebral fractures. However, a Women’s Health Initiative (WHI) study reported a higher risk for cardiovascular disease, thromboembolic event, stroke, and breast cancer with a combined treatment of estrogens and progestin [44]. Following the results of the WHI study, new guidelines recommended hormone supplements with lower dose for the shortest amount of time. The Food and Drug Administration in the United States suggests using HRT only for hot flashes and vaginal dryness [45]. HRT can also be used for the prevention of osteoporosis when other treatments are not available [45].
2. Testosterone
Low testosterone levels in older men has been associated with various age-associated conditions [46,47]. Sarcopenia and osteoporosis are more frequent in older men with low plasma testosterone levels [48,49]. Furthermore, several studies have demonstrated a relationship between low testosterone levels and mild cognitive impairment and Alzheimer’s disease [50]. Thus, testosterone replacement therapy is beneficial as it can increase muscle mass, strength, and BMD in elderly men [51]. Cognitive function, including verbal, spatial, working memory, and visuospatial function, was improved by testosterone supplementation in elderly men [45]. One of the adverse effects of testosterone administration is polycythemia. For this reason, patients undergoing testosterone replacement therapy should have their hemoglobin or hematocrit levels checked every 6 months for a total duration of 18 months. Another main concern with testosterone replacement therapy is the potential risk of aggravating prostate cancer. Animal studies have reported that prostate cancer growth was stimulated by testosterone administration [52]. Thus, although recent studies have failed to confirm a relationship between testosterone levels and the risk of prostate cancer, testosterone replacement therapy should be seriously reconsidered in patients with active prostate cancer [53,54]. In general, the absolute contraindications of testosterone replacement therapy are as follows: suspected prostate cancer, severe symptoms of the lower urinary tract such as an International Prostate Symptom Score >19, hematocrit >50%, ischemic heart disease in the preceding 6 months, poorly controlled congestive heart failure, and untreated sleep apnea [45].
3. Dehydroepiandrosterone
The dehydroepiandrosterone (DHEA) and its metabolite DHEA-sulfate are precursors for sex hormones produced by the adrenal gland, which are subsequently transformed into androgen or estrogen in the target tissue [45]. The decline of plasma DHEA levels with age is clinically associated with various age-related conditions [55]. Since ovarian production of estrogen decreases in postmenopausal women, the adrenal gland is the only source of estrogen through the peripheral conversion of DHEA [56]. In previous studies, DHEA supplementation was positively associated with muscle mass, muscle strength, physical performance, and BMD in both men and women [57-60]. Furthermore, DHEA administration has demonstrated beneficial effects on mood and sexual function [61,62]. However, the relationship between DHEA and cognitive function has not been sufficiently researched [45]. Recent studies reported that low DHEA levels are related to a higher risk for atherosclerosis, heart failure, cardiovascular complications, and overall mortality [63]. Nevertheless, the relationship between DHEA and cardiovascular disease risk factors is still controversial. The adverse effects of DHEA are minimal, such as mild acne, seborrhea, facial hair growth, and ankle swelling in women [64,65]. There was no significant effect on hormone-dependent tumors such as breast and prostate cancer [56,66], but longer and larger studies are warranted to sufficiently prove the safety of DHEA. DHEA is not allowed in the Republic of Korea even though it is one of the most widely used anti-aging hormones in the United States.
Vitamin D is a significant pro-hormone for optimal intestinal calcium absorption for the mineralization of bone [77]. Recently, many studies have revealed numerous positive effects of vitamin D use in the elderly population. Vitamin D deficiency in the elderly is associated with decreased cognitive function, a higher risk of Alzheimer’s disease [78], loss of muscle mass and function [79], and osteoporosis. Cross-sectional studies have demonstrated that a low level of vitamin D is related to a higher risk of cardiovascular diseases such as hypertension, heart failure, and ischemic heart disease [80,81]. However, the effects of vitamin D as a supplement are still controversial. One study demonstrated that a high serum vitamin D concentration is associated with high atherosclerosis cardiovascular disease risk scores [82].
Since vitamin D production is usually stimulated by adequate sun exposure, vitamin D levels tend to be lower in elderly people with reduced outside activity. Vitamin D therapy in the elderly was shown to improve muscle mass and performance, and to a reduced the rate of falls [79]. Furthermore, a recent study reported that vitamin D also has an anti-cancer effect by inhibiting cancer cell growth in several types of cancer [83]. In this regard, numerous agencies and scientific organizations have developed recommendations for vitamin D therapy and also provide guidance on optimal serum 25-hydroxyvitamin D (25[OH]D) concentrations. The general target for the 25(OH)D concentration is above 30 ng/mL, and the replacement dose can vary, ranging from between 400 and 2,000 IU/d depending on age, body weight, disease status, and ethnicity [84]. Vitamin D intake through natural food sources such as milk, beverages made from soy, almonds, and coconuts is also important in elderly people with low vitamin D levels [84].
CONCLUSION
Anti-aging medicine is a growing field in locations with an aging population, particularly in developed countries. Available anti-aging interventions are categorized in Table 1 according to their mechanisms of action. CRM define compounds that imitate the outcome of calorie restriction, and these include the activator of AMPK (metformin), inhibitor of GH/IGF-1 axis (pegvisomant), inhibitor of mTOR (rapamycin), and activator of the sirtuin pathway (resveratrol). Hormonal replacement such as estrogen, progestin, testosterone, and DHEA in the elderly have been widely used to improve various symptoms associated with frailty, body composition, cardiometabolic diseases, neurodegenerative diseases, and quality of life. Since HRT can increase the risk of thromboembolism or some types of cancer, it should be used with precautions. The composition of healthy gut microbiota through prebiotic/probiotics and FMT has a great potential for anti-aging medicine. Furthermore, vitamin D is expected to be a main anti-aging medicine in the near future due to its numerous positive effects in elderly population.