Endocrine function in naturally long-living small mammals

Abstract

The complex, highly integrative endocrine system regulates all aspects of somatic maintenance and reproduction and has been widely implicated as an important determinant of longevity in short-lived traditional model organisms of aging research. Genetic or experimental manipulation of hormone profiles in mice has been proven to definitively alter longevity. These hormonally induced lifespan extension mechanisms may not necessarily be relevant to humans and other long-lived organisms that naturally show successful slow aging. Long-lived species may have evolved novel anti-aging defenses germane to naturally retarding the aging process. Here, we examine the available endocrine data associated with the vitamin D, insulin, glucocorticoid and thyroid endocrine systems of naturally long-living small mammals. Generally, long-living rodents and bats maintain tightly regulated lower basal levels of these key pleiotropic hormones than shorter lived rodents. Similarities with genetically manipulated long-lived rodent models of aging suggest that evolutionary well-conserved hormonal mechanisms are integrally involved in lifespan determination.

Fig. 1

Maximum lifespan as a function of body mass of small mammals. Please note that most bat species are long-lived while only a few rodent species acquire similar longevity. Most of these long-living rodents are burrow dwelling rodents, like mole-rats and squirrels.

Fig. 2

Synthesis, metabolism and functions of vitamin D. Vitamin D can be synthesized in skin during exposure to solar ultraviolet B radiation, or acquired by eating foods rich in animal fats. Vitamin D is converted by 25-hydroxylase to 25-hydroxyvitamin D [25(OH)D]. This major circulating metabolite, although biologically inactive is used as an indicator of vitamin D status. 25(OH)D is hydroxylated by1-alpha-hydroxylase to the biologically active form, 1,25-dihydroxyvitamin D [1,25(OH)₂D]. Serum phosphorus, calcium, 1,25(OH)₂D itself, Klotho, fibroblast growth factor 23 (FGF-23), and other factors regulate 1,25(OH)₂D synthesis. Renal 1,25(OH)₂D enhances intestinal calcium absorption by promoting the expression of the epithelial calcium channels and calcium-binding proteins. Furthermore, renal 1,25(OH)₂D is active in bone where it is recognized by its receptor in osteoblasts, causing an increase in the expression of nuclear factor-{kappa}B ligand. This in turn promotes osteoclastic activity and assists in both the maintenance of serum calcium and phosphorus as well as in bone remodelling. The 1,25(OH)₂D produced in the kidney enters the circulation and can down-regulate renin production in the kidney and stimulate insulin secretion in the beta islet cells of the pancreas. Extra-renal 1,25(OH)₂D synthesis acts locally to direct normal cell proliferation by regulating a variety of genes that control proliferation, including p21 and p27, as well as genes that inhibit angiogenesis and induce differentiation and apoptosis. Modulation of the immune response is facilitated by influencing T lymphocyte synthesis and cytokine secretions, and by activating B lymphocytes thereby regulating immunoglobulin synthesis, as well as through increasing the expression of cathelicidin, a peptide capable of promoting innate immunity. Clearly actions of vitamin D may play an integral part in determining rates of organismal aging.

Fig. 3

Glucose tolerance of naked mole-rats and mice. Glucose tolerance tests were measured in young healthy naked mole-rats and mice that had been fasted overnight. Animals were given intraperitoneal injections of either 2g glucose per kg body weight or an equivalent volume of 0.9% saline (control). Blood samples were taken immediately prior to injection and again at set time intervals after the glucose load. Blood glucose of naked mole-rats rose more slowly than mice and remained elevated for considerably longer, suggesting that naked mole-rats show some degree of either insulin insensitivity or insulin deficiency.

Fig. 4

Free thyroxine levels of four rodents with disparate longevity (mice, 3y; guinea pigs 8y; damara mole-rats 15y and naked mole-rats 28.3y) show a negative correlation with maximum lifespan potential. Blood samples were collected at the same time of day from animals housed in our animal facility. Free thyroxine was measured using commercially available kits.

Fig. 5

Low hormone levels may promote slow aging through modulation of body temperature, glucose metabolism and membrane composition, membrane permeability and signal transduction pathways.