Why men age faster but reproduce longer than women: mTOR and evolutionary perspectives

Abstract

Women live longer than men. Yet, it is believed that men do not age faster than women but simply are weaker at every age. In contrast, I discuss that men age faster. From evolutionary perspective, high accidental death rate in young males is compatible with fast aging. Mechanistically, hyper-activated mTOR (Target of Rapamycin) may render young males robust at the cost of accelerated aging. But if women age slower, why then is it women who have menopause? Some believe that menopause is programmed and purposeful (grandmother theory). In contrast, I discuss how menopause is not programmed but rather is an aimless continuation of the same program that initially starts reproduction at puberty. This quasi-program causes over-activation of female reproductive system, which is very vulnerable to over-activation. Mechanisms of aging and menopause are discussed.

Figure 1.. Program of growth and quasi-program of aging.

The TOR pathway is activated by growth factors, hormones and nutrients. This activation is beneficial early in life by stimulating growth and muscle hypertrophy. Evolutionary perspective: This was especially important for prehistoric men, living in dangerous environment that required physical strength. mTOR is involved in aging later in life, but most men died young from accidental death. Thus, robustness early in life is associated with accelerated aging.

Figure 2.. Negative feedback and insulin resistance.

TOR is activated by nutrients and insulin and in turn causes depletion of IRS1/2 and insulin resistance. Whereas nutrients activate TOR, low nutrients and metformin deactivate TOR.

Figure 3.. From programmed puberty to quasi-programmed menopause.

For simplicity, only the FSH-estrogen feedback loop is shown. FSH stimulates follicles and production of estrogens (Est). Estrogens inhibit FSH production (negative feedback). (A) In girls, the hypothalamus is extremely sensitive to estrogens and even low levels of estrogens inhibit FSH. (B) The onset of menstrual cycle. While the hypothalamus is becoming resistant to estrogens, FSH stimulates the ovaries and estrogen production. Progressive activation of follicles from the dormant pool serves as the source of fertilizable ova. (C) Pre-menopause. While the hypothalamus is becoming progressively resistant to estrogens, FSH progressively over-stimulates the ovaries. (D) The ovaries fail. Menopause occurs when the primordial follicle pool is exhausted. Estrogen levels drop. The feedback between hypothalamus and the ovaries is disrupted.

Figure 4.. Program of puberty and quasi-program of menopause.

The TOR pathway in the hypothalamus and the ovary is activated by growth factors, hormones (leptin, estrogens and FSH, LH, respectively) and nutrients. This activation starts menarche and then leads to menopause.