Garbage catastrophe theory of aging: imperfect removal of oxidative damage?

Abstract

Increasing evidence suggests an important role of oxidant-induced damage in the progress of senescent changes, providing support for the free radical theory of aging proposed by Harman in 1956. However, considering that biological organisms continuously renew their structures, it is not clear why oxidative damage should accumulate with age. No strong evidence has been provided in favor of the concept of aging as an accumulation of synthetic errors (e.g. Orgel's 'error-catastrophe' theory and the somatic mutation theory). Rather, we believe that the process of aging may derive from imperfect clearance of oxidatively damaged, relatively indigestible material, the accumulation of which further hinders cellular catabolic and anabolic functions. From this perspective, it might be predicted that: (i) suppression of oxidative damage would enhance longevity; (ii) accumulation of incompletely digested material (e.g. lipofuscin pigment) would interfere with cellular functions and increase probability of death; (iii) rejuvenation during reproduction is mainly provided by dilution of undigested material associated with intensive growth of the developing organism; and (iv) age-related damage starts to accumulate substantially when development is complete, and mainly affects postmitotic, cells and extracellular matrix, not proliferating cells. There is abundant support for all these predictions.

Interactive effects of temperature and salinity on shell formation and general condition in Baltic Sea Mytilus edulis and Arctica islandica

“…Hyper-or hypo saline conditions may cause physiological stress as they force the animal to invest more energy into ion regulatory processes (Silva & Wright 1994, Deaton 2001 , Abele & Puntarulo 2004. Removal of the damaged cell structures by proteasomes and lysosomes requires energy, is often incomplete, and can result in waste accumulation (Terman 2001, Brunk & Terman 2002b). The 'aging pigment' lipofuscin represents such damaged cell structures, mainly oxidised proteins and lipids, which were incompletely de graded.…”

“…The 'aging pigment' lipofuscin represents such damaged cell structures, mainly oxidised proteins and lipids, which were incompletely de graded. Largely indigestible, lipofuscin accumulates in the lysosomes (Terman 2001, Brunk & Terman 2002b and can be used as a biomarker for lifetime oxidative cell damage (Winston 1991, Brunk & Terman 2002a, Philipp et al 2006. In marine molluscs, increased lipofuscin accumulation has been measured under physiological stress caused by pollution (Krishnakumar et al 1997, Kagley et al 2003, Aarab et al 2008 or high temperatures (Abele et al 1998).…”

Autophagy, organelles and ageing

“…Although attractive, both hypotheses generally failed. Somatic mutations could not explain the variety of cellular senescent changes, and no apparent increase in the formation of defective enzymatic proteins was found in relation to time (reviewed in [3,19]). Obviously, other explanations for the fact that ageing postmitotic cells do accumulate structures that have been damaged by oxidation must be found.…”

“…Malfunction of essential postmitotic cells leads to degeneration of the whole organism, shown by the decreased adaptability and increased probability of disease and death, which are common characteristics of an aged (senescent) individual. Most dividing cells, such as stem and progenitor cells, as well as short-lived postmitotic cells that differentiate from those cells (eg enterocytes and peripheral blood cells) remain in good shape, even at the end of a normal lifespan (reviewed in [3]). This is because repetitive division of stem and progenitor cells results in a continuous dilution of damaged macromolecules and organelles (here referred to as biological 'garbage' or 'waste'), while differentiated cells are frequently replaced and therefore do not accumulate any considerable amount of such 'garbage' [4,5].…”

“…The degradation of such structures takes place through the action of calpains, proteasomes or by different forms of autophagy (autophagocytosis), implying that any cell is a permanent construction site where old structures are torn apart and replaced by newly synthesized ones, using the basic parts of the degraded structures as building blocks for new assemblies [3,5]. Theoretically, these processes should keep postmitotic cells healthy and in good function as long as nutrition is provided and disease does not strike.…”