Review
Aging: Central role for autophagy and the lysosomal degradative system

https://doi.org/10.1016/j.arr.2009.05.001Get rights and content

Abstract

The lysosomal network is the major intracellular proteolytic system accounting for more than 98% of long-lived bulk protein degradation and recycling particularly in tissues such as liver and muscles. Lysosomes are the final destination of intracellular damaged structures, identified and sequestered by the processes of macroautophagy and chaperone-mediated autophagy (CMA). In the process of macroautophagy, long-lived proteins and other macromolecular aggregates and damaged intracellular organelles are first engulfed by autophagosomes. Autophagosomes themselves have limited degrading capacity and rely on fusion with lysosomes. Unlike macroautophagy, CMA does not require intermediate vesicle formation and the cytosolic proteins recognized by this pathway are directly translocated to the lysosomal membrane. Aging is a universal phenomenon characterized by progressive deterioration of cells and organs due to accumulation of macromolecular and organelle damage. The continuous removal of worn-out components and replacement with newly synthesized ones ensures cellular homeostasis and delays the aging process. Growing evidence indicate that the rate of autophagosome formation and maturation and the efficiency of autophagosome/lysosome fusion decline with age. In addition, a progressive increase in intralysosomal concentration of free radicals and the age pigment lipofuscin further diminish the efficiency of lysosomal protein degradation. Therefore, integrity of the autophagosomal-lysosomal network appears to be critical in the progression of aging. Discovery of the genes involved in the process of autophagy has provided insight into the various molecular pathways that may be involved in aging and senescence. In this review, we discuss the cellular and molecular mechanisms involved in autophagy and the role of autophagosome/lysosome network in the aging process.

Introduction

In the past two decades, there had been a constant accumulation of new knowledge in the field of research studying the aging process. The study of the biological basis of ageing, biogerontology, has so far unveiled mysteries of ageing by describing age-related changes in organisms, organs, tissues, cells and macromolecules (Troen, 2003). However, despite intense research, the molecular basis of the processes that cause loss of bodily functions and degeneration of cells and tissues is still unresolved. Aging is an essential, inevitable physiological phenomenon characterized by a progressive accumulation of deleterious molecular damages in cells and tissues during the post-maturational deterioration, which decreases the ability to survive and increases risk of death (Rajawat and Bossis, 2008). The aging process has many facets and multiple causes. The primary molecular phenotype of aging is the stochastic occurrence and accumulation of molecular damage leading to a progressive increase in molecular heterogeneity and functional impairment (Rattan, 2006). The failure of maintenance and repair pathways, effectively determines the course of aging, the origin of age-related diseases and eventual death (Holliday, 1995, Holliday, 2000, Rattan, 2006, Rattan and Clark, 2005). Predetermined genetic factors, environmental influences, and certain diseases contribute to the process of aging. Accumulation of worn-out organelles and various cellular substructures over time reduces the cellular and molecular efficiency of various biological processes that are required to maintain homeostasis and survival.

Malfunctions in the biological processes required for the maintenance, repair and turnover pathways may be the main cause of the cumulative cellular damages during aging (Sohal et al., 1994). Aging, senescence and death are the final manifestations of unsuccessful homeostasis or failure of homeodynamics (Holliday, 2007, Rattan, 2006).

In various organisms, different types of cells have diverse kinds of machinery which accomplish their assigned functions. However, these heterogeneous cell populations have to operate in unison for proper functioning, adaptation and survival in harsh environments. During the lifespan of an organism, cells are subjected to various destructive forces, which may originate from either internal or external sources. The result of continuous exposure to these harmful forces is progressive accumulation of lesions. Over time these lesions become detrimental to cell and tissue survival. The precise molecular mechanism of aging is not yet completely understood. The elements that are responsible for oxidative damage and improper housekeeping are considered the main contributory causes and play pivotal roles in cell survival.

Section snippets

Characteristics of aging

In general, there are some common and universally accepted characteristics that manifest during the process of aging, such as, increased mortality after maturation (Gompertz, 1825), changes in the biochemical composition of tissues (Florini, 1981, Strehler, 1977), progressive decrease in physiological capacity (Lakatta, 1990, Shock, 1985, Lindeman et al., 1985), reduced ability to respond adaptively to environmental stimuli (Adelman et al., 1978) and increased susceptibility and vulnerability

Theories of aging

Aging is a multifactorial process and attempts at understanding the fundamental causes of aging are limited by the complexity of the problem (Kirkwood, 2005). Aging is manifested and easily observed at the organism level. However, studying the aging process at the cellular and molecular level is more complicated and subject to confounding experimental and environmental factors (Dice, 1993). The lack of precise, well defined and reliable cellular and biochemical markers of aging has hindered

Lysosomes

The concept of cellular protein turnover is about half a century old (Ciechanover, 2005a). The quest to identify a mechanism or enzymes responsible for maintaining the cellular protein pool started the era of cellular organelles discoveries. More than 50 years ago, this search led Belgian cytologist Christian de Duve to discover lysosomes, as a result of studying the intracellular distribution of enzymes using centrifugal fractionation (de Duve, 2005). The term lysosome derives from the Greek

Lysosomes and aging

Age-related decline in overall proteolytic activity has been observed in almost all organisms and progressive intracellular accumulation of damaged proteins with age has been extensively documented (Ward, 2002). Thus, the activity of lysosomes becomes pivotal in adequately removing damaged products in aged organisms and explains the reason why lysosomes are at center stage of aging research looking for possible explanation for decreased proteolysis with age (Martinez-Vicente et al., 2005).

Most

Autophagy

Autophagy (derived from the Greek meaning “to eat oneself”) is present in all eukaryotic cells and is evolutionarily conserved from yeast to humans (Levine and Klionsky, 2004). Autophagy is a ubiquitous catabolic process that involves the bulk degradation of cytoplasmic components through a lysosomal pathway. This process is characterized by the engulfment of part of the cytoplasm inside double-membrane vesicles called autophagosomes. Autophagosomes subsequently fuse with lysosomes to form an

Autophagy and aging

Genetic studies in yeast were pivotal in identifying the role of autophagy genes in cellular aging. As a result of this discovery, yeast homologues were identified in higher eukaryotic organisms that fueled aging-related research in more evolutionary advanced species. C. elegans has been extensively used as a model organism to study the mechanisms controlling life span and has provided the first evidence linking autophagy to the aging process. In this organism, RNA-i mediated depletion of

Perspective

Aging is an intrinsic property of biological systems that results from the accumulation of defects after exposure to harsh environmental conditions, such as, nutrient limitation, temperature extremes, osmotic changes, hormone stimulation, radiation exposure and pollutants. Aging phenotypes were described long before the molecular basis of the phenomenon was understood. Studying the molecular basis of aging poses many challenges because it involves interactions at many levels of organization

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