A Tale of Two Concepts: Harmonizing the Free Radical and Antagonistic Pleiotropy Theories of Aging

Abstract

Significance: The two foremost concepts of aging are the mechanistic free radical theory (FRT) of how we age and the evolutionary antagonistic pleiotropy theory (APT) of why we age. Both date from the late 1950s. The FRT holds that reactive oxygen species (ROS) are the principal contributors to the lifelong cumulative damage suffered by cells, whereas the APT is generally understood as positing that genes that are good for young organisms can take over a population even if they are bad for the old organisms. Recent Advances: Here, we provide a common ground for the two theories by showing how aging can result from the inherent chemical reactivity of many biomolecules, not just ROS, which imposes a fundamental constraint on biological evolution. Chemically reactive metabolites spontaneously modify slowly renewable macromolecules in a continuous way over time; the resulting buildup of damage wrought by the genes coding for enzymes that generate such small molecules eventually masquerades as late-acting pleiotropic effects. In aerobic organisms, ROS are major agents of this damage but they are far from alone.

Critical issues: Being related to two sides of the same phenomenon, these theories should be compatible. However, the interface between them is obscured by the FRT mistaking a subset of damaging processes for the whole, and the APT mistaking a cumulative quantitative process for a qualitative switch.

Future directions: The manifestations of ROS-mediated cumulative chemical damage at the population level may include the often-observed negative correlation between fitness and the rate of its decline with increasing age, further linking FRT and APT. Antioxid. Redox Signal. 29, 1003-1017.

Keywords: aging; chemistry; evolution; metabolism; oxygen; reactive oxygen species; theory.

FIG. 1.

Some milestones on the parallel tracks of FRT and APT of aging with focus on topics discussed in this article. FRT events are above and APT events are below the timeline. APT, antagonistic pleiotropy theory; FRT, free radical theory. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 2.

Oxygen interference with an anaerobic pathway of protein damage by glycation. (I) Reversible Schiff base formation; (II) Irreversible Amadori rearrangement; (III) Enolization; (IV) Double bond migration; (V) Dehydration; (VI) Condensation of α-dicarbonyl with arginine; (VII) Enediol oxidation (associated with the generation of reactive oxygen species, including hydrogen peroxide); (VIII) Oxidative cleavage of α-dicarbonyl. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 3.

The history of molecular oxygen and life on the Earth. The red and green curves on the left show the highest and lowest PO₂ estimates, respectively (based on https://en.wikipedia.org/wiki/Geological_history_of_oxygen). To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 4.

Evolutionary relationship between the ability for total regeneration and aging. Dashed phylogenetic branches indicate uncertain positions. Note that most metazoan phyla have not been studied with regard to aging. Based on Telford et al. (127) and Bely (7). To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 5.

Illustrative plots of changes in lifespan depending on changes in the parameters of the Gompertz–Makeham law. Upper row: survivorship curves, n(t); middle row: age-at-death (lifespan) distributions, −dn/dt; lower row: logarithms of mortality force ln[−dn/(dt × n(t))]. Lifespan may increase because (A) the age-independent mortality C decreases; (B) the rate of aging γ decreases; or (C) the initial vigor (1/λ) increases. The column (D) shows a case when γ and λ are linked according to the SM correlation: greater initial vigor is associated with faster aging rate; for example, an increase in the availability or use of aerobic energy is associated with a greater rate of damage to macromolecules. On the semilogarithmic plots of μ versus t (the lower row), increases in C make the plots increasingly curved, changes in γ are manifested in plot slopes, and changes in λ in the parallel shifts of the plots, whereas negatively correlated changes in λ and γ make the plots converge. Note that when C is small, its changes may mimic patterns that correspond to the SM correlation. SM, Strehler–Mildvan.

FIG. 6.

Relationships between pleiotropic beneficial and antagonistic effects of two hypothetical genes. Gene A codes for the enzyme that makes metabolite M2, which can give rise spontaneously to a damaging product D. D can directly damage DNA, thus making Gene A antagonistically pleiotropic, and can induce the aggregation of the protein product of Gene B, thus making Gene B antagonistically pleiotropic. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars