Alternative Perspectives on Aging in Caenorhabditis elegans: Reactive Oxygen Species or Hyperfunction?

Abstract

Significance: The biological mechanisms at the heart of the aging process are a long-standing mystery. An influential theory has it that aging is the result of an accumulation of molecular damage, caused in particular by reactive oxygen species produced by mitochondria. This theory also predicts that processes that protect against oxidative damage (involving detoxification, repair, and turnover) protect against aging and increase lifespan.

Recent advances: However, recent tests of the oxidative damage theory, many using the short-lived nematode worm Caenorhabditis elegans, have often failed to support the theory. This motivates consideration of alternative models. One new theory, conceived by M.V. Blagosklonny, proposes that aging is caused by hyperfunction, that is, overactivity during adulthood of processes (particularly biosynthetic) that contribute to development and reproduction. Such hyperfunction can lead to hypertrophy-associated pathologies, which cause the age increase in death.

Critical issues: Here we assess whether the hyperfunction theory is at all consistent with what is known about C. elegans aging, and conclude that it is. In particular, during adulthood, C. elegans shows a number of changes that may reflect pathology and/or hyperfunction. Such changes seem to contribute to death, at least in some cases (e.g., yolk accumulation).

Future directions: Our assessment suggests that the hyperfunction theory is a plausible alternative to the molecular damage theory to explain aging in C. elegans.

FIG. 1.

The hyperfunction theory of aging. (A) Simplified representation of molecular damage theory (including oxidative damage theory). (B) Simplified representation of hyperfunction theory. (C) Mode of action of target of rapamycin (TOR) pathway on aging, based on the molecular damage theory. (D) Mode of action of TOR pathway on aging, based on the hyperfunction theory. Derived from (5). IIS, insulin/IGF-1 signaling.

FIG. 2.

Explanation for effects of dietary restriction (DR) in terms of the bloated soma theory. (A) Prior interpretation in terms of disposable soma theory. (B) New interpretation in terms of bloated soma theory (incorporating hyperfunction theory). Based on (6). IGF-1, insulin-like growth factor 1.

FIG. 3.

Evidence for hypertrophy during aging in Caenorhabditis elegans. This figure shows six examples of age change that involves hypertrophy, as follows: (i) accumulation and redistribution of yolk (shaded area, high levels of yolk [VIT-2::GFP fluorescence]); (ii) stacking of oocytes in the gonad; (iii) appearance of tumor-like, intrauterine masses, a likely consequence of runaway endoreduplication in unfertilized oocytes (O, oocyte; T, tumor); (iv) cuticular hypertrophy (C, cuticle; H, hypodermis); (v) neurite outgrowth (NO, neurite outgrowth); and (vi) lipid droplet accumulation (here in aging muscle, L, lipid droplet; M, muscle). In each part, young adult worm is shown above and an older worm below. Redrawn after published observations (12, 15, 18, 24, 27, 37, 48).

FIG. 4.

Age-associated gonadal atrophy. (A–D) progressive stages of atrophy of hermaphrodite gonad. (A) 1-day-old adult, healthy, full-sized gonad; (B) 5-day-old adult, gonad slightly atrophied; (C) 7-day-old adult, shrunken, but largely intact gonad; (D) 9-day-old adult, fragmented gonad.

FIG. 5.

Relative contributions of damage and hyperfunction in mammals and nematodes. This scheme describes the hypothesis that DNA damage and hyperfunction are predominant primary determinants of mammalian aging, while in C. elegans hyperfunction is particularly severe, such that molecular damage plays no primary role at all.