Elsevier

Molecular Aspects of Medicine

Volume 27, Issues 5–6, October–December 2006, Pages 455-470
Molecular Aspects of Medicine

Review
The involvement of macroautophagy in aging and anti-aging interventions

https://doi.org/10.1016/j.mam.2006.08.003Get rights and content

Abstract

Macroautophagy is a process that sequesters and degrades organelles and macromolecular constituents of cytoplasm for cellular restructuring and repair, and as a source of nutrients for metabolic use in early starvation. Extensive evidence has been reported that macroautophagy process declines with increasing age. This impairment, probably due to ad libitum feeding, may cause accumulation of altered structures leading to the age-related decline in cell functions. It has been suggested that caloric restriction (CR) and disruption of insulin-like signals contrast the process of aging by prolonged stimulation of macroautophagy. According to this hypothesis, it is shown that life-long weekly administration of an anti-lipolytic drug decreases glucose and insulin levels, stimulates autophagy and intensifies anti-aging effects of submaximal CR.

Introduction

Aging is characterized by a progressive accumulation of damaged macromolecules, organelles and cytomembranes which may account for the age-associated malfunctioning of many biological processes. The inefficiency and failure of maintenance, repair and turnover pathways may be the main cause of damage accumulation during aging (Sohal et al., 1994, Grune, 2000). Turnover of cellular components is based on a homeostatic balance between synthesis and degradation: eukaryotic cells are equipped with several degradation system, a major of which is the process of macroautophagy.

Macroautophagy, generally referred to as macroautophagy, is a universal, dynamic process which takes place in all eukaryotic cells, that involves a rearrangement of subcellular membranes to sequester cytoplasm and organelles for delivery to the lysosome or vacuole, where the sequestered cargo is degraded and recycled (Yorimitsu and Klionsky, 2005).

The primary roles of macroautophagy are baseline turnover of intracellular proteins and organelles, production of amino acids in nutrient emergency, and regression of retired tissues. These functions guarantee rejuvenation and adaptation to adverse conditions, and even underlie dynamic processes such as development/metamorphosis (Mizushima, 2005).

The major role of macroautophagy is starvation response. In fact, macroautophagy deficient yeasts succumb readily to starvation (Tsukada and Ohsumi, 1993) and in mammalian, macroautophagy is induced in almost all organs in response to nutrient starvation (Mizushima et al., 2004) in order to maintain an amino acid pool for gluconeogenesis and for synthesis of proteins essential to survival (Yoshimori, 2004).

Extensive research on mammalian cells during the last three decades showed that macroautophagy and lysosomal proteolysis are induced by lower amino acid and insulin levels during fasting, whereas the higher (postprandial) levels of insulin fully suppress macroautophagy in the physiological range of plasma amino acid concentration (Mortimore and Poso, 1987, Mortimore et al., 1989, Seglen and Bohley, 1992).

Macroautophagy is also required for normal turnover of cellular components particularly in response to starvation (Mortimore and Poso, 1987). Indeed, the bulk degradation of long-lived proteins (90% of cellular protein) is mediated by macroautophagy and the process is the only mechanism for the degradation of membranes and organelles (Pfeifer, 1978), including mitochondria (Rodriguez-Enriquez et al., 2004) and peroxisomes (Locci-Cubeddu et al., 1985).

Macroautophagy has been demonstrated to play an important role in the degradation of excess or injured organelles (Yoshimori, 2004). In addition incubation of primary cells and cell lines in the absence of serum promotes macroautophagy of mitochondria with deleterious mtDNA mutations but spares their normal counterparts (Gu et al., 2004).

In conclusion macroautophagy is a cell-mechanism involved in both the survival during starvation and the turnover of macromolecules, cytomembranes and organelles (Bergamini et al., 2004a, Bergamini et al., 2004b).

Experimental evidence was shown that impairment of macroautophagy is involved in the process of aging: in this review we focus on the consequences of macroautophagy impairment and on the interventions that may contrast aging by stimulation of macroautophagy.

Section snippets

The aging process

Aging is a progressive deterioration of physiological function that impairs the ability of an organism to maintain homeostasis and consequently increases the organism’s susceptibility to disease and death (Harman, 2001).

Many theories of aging are based on the concept that damage, either due to normal toxic by-products of metabolism or inefficient repair/defensive systems, accumulates throughout the entire lifespan and causes aging.

The oxidative damage theory of aging postulates that the

Intervention in aging: caloric restriction and disruption of insulin-like signaling

Caloric restriction (CR) has a positive effect on the median and maximum lifespan and health span of rodents and various invertebrate – protozoa, flies, water fleas, nematodes, rotifers and spiders- and vertebrate species– fish, hamsters, dogs (Masoro, 2002). CR refers to the reduction in caloric intake while maintaining essential nutrient requirements. Traditionally, experimental mammalian models of caloric restriction involve a reduction in caloric intake by 40% of the ad libitum diet

Macroautophagy in aging and anti-aging intervention

Function of macroautophagy declines with increasing age. By the use of a perfused rat liver preparation with no added amino acid, Ward reported that the maximum rate of macroautophagic degradation of long-lived protein is paramount by age 6 months and then shows a significant and progressive age-related decline (Ward, 1988).

Similar data were obtained with isolated rat liver cells by Donati et al. (2001a). These authors showed that changes in regulation of macroautophagic proteolysis by the

Macroautophagy as an anti-aging cell mechanism

Macroautophagy may be involved in preventing the “waste” accumulation within cells by its effective function on the turnover of cell components and disposal of damaged protein or organelles. If stimulated effectively, this cell housekeeping function may prevent any age-related physiological decline [e.g. immunosenescence (Cuervo et al., 2005)] and pathologies [e.g. neurodegenerative diseases (Komatsu et al., 2006)].

Pharmacological intensification of suppression of aging (PISA) by stimulation of macroautophagy

The administration of an anti-lipolytic agent to fasting rats causes a sudden decline of free fatty acids and glucose and an increase in the glucagon/insulin ratio leading to an intensification of autophagic proteolysis, as shown by an increase in liver autophagic compartment and a release of valine in plasma (Pollera et al., 1990, Bergamini and Kovacs, 1990, Bergamini et al., 1993). Treatment increases the expression of LC3, a well known marker of autophagosomes (Donati et al., in press). This

Conclusion

Data support the hypothesis that macroautophagy has a major role in the retardation of the aging process by anti-aging interventions. According to this hypothesis, ad libitum feeding may inhibit, and caloric restriction and disruption of insulin-like signaling may intensify, macroautophagy throughout the life. Data with the PISA model show that safe pharmacological procedure are available to intensify the process (Fig. 1).

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