Programmed Aging of Mammals: Proof of Concept and Prospects of Biochemical Approaches for Anti-aging Therapy.

(i) In 2015-2017 we compared possible reasons for longevity of two mammalian highly social species, i.e. naked mole rats and humans. We proposed that in both cases longevity is a result of neoteny, prolongation of youth by deceleration of late ontogeny (Skulachev, V. P. (2015) Abst. 11th Conf. on Mitochondrial Physiology (MiP2015), Lucni Bouda, Czech Republic, pp. 64-66; Skulachev, V. P., Holtze, S., Vyssokikh, M. Y., Bakeeva, L. E., Skulachev, M. V., Markov, A. V., Hildebrandt, T. B., and Sadovnichii, V. A. (2017) Physiol. Rev., 97, 699-720). Both naked mole rats and humans strongly decreased the pressure of natural selection, although in two different manners. Naked mole rats preferred an "aristocratic" pathway when reproduction (and, hence, involvement in evolution) is monopolized by the queen and her several husbands. Huge number of subordinates who have no right to take part in reproduction and hence in evolution serves the small queen's family. Humans used an alternative, "democratic" pathway, namely technical progress facilitating adaptation to the changing environmental conditions. This pathway is open to all humankind. (ii) As a result, aging as a mechanism increasing evolvability by means of facilitation of natural selection became unnecessary for naked mole rats and humans due to strong attenuation of this selection. This is apparently why aging became a counterproductive atavism for these two species and was strongly shifted to late ages. This shift is direct evidence of the hypothesis that aging is programmed, being the last step of late ontogeny. (iii) Further deceleration of aging for humans by means of neoteny is unrealistic since the development of neoteny probably takes million years. (iv) However, if biological aging is a program, an alternative and much simpler way to avoid it seems possible. We mean inhibition of an essential step of this program. (v) At present, the most probable scheme of the aging program assumes that it is a mechanism of slow poisoning of an organism by reactive oxygen species produced by mitochondria. If this is the case, a mitochondria-targeted antioxidant might be an inhibitor of the aging program. During the last 12 years, such an antioxidant, namely SkQ1, was synthesized and studied in detail in our group. It consists of plastoquinone and decyltriphenylphosphonium (a penetrating cation responsible for electrophoretic accumulation of SkQ1 in mitochondria). It was shown that long-term treatment with SkQ1 increased the lifespan of plants, fungi, invertebrates, fish, and mammals. Moreover, SkQ1 is effective in the therapy of various age-related diseases. It was also shown that a single SkQ1 injection could save life in certain models of sudden death of animals. (vi) A tentative scheme is proposed considering aging as a process of chronic phenoptosis, which eventually results in initiation of acute phenoptosis and death. This scheme also suggests that under certain conditions chronic phenoptosis can be neutralized by an anti-aging program that is activated by food restriction regarded by an organism as a signal of starvation. As for acute phenoptosis, it is apparently controlled by receptors responsible for measuring key parameters of homeostasis. The first experimental indications have been already obtained indicating that both chronic and acute phenoptosis are suppressed by SkQ1.