ReviewAging: Central role for autophagy and the lysosomal degradative system
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
References (212)
- et al.
Membrane protein degradation by AAA proteases in mitochondria
Biochim. Biophys. Acta
(2002) - et al.
Mitochondria, oxidants, and aging
Cell
(2005) - et al.
Lipofuscin: mechanisms of age-related accumulation and influence on cell functions
Free Radic. Biol. Med.
(2002) - et al.
Impairment of proteasome structure and function in aging
Int. J. Biochem. Cell Biol.
(2002) - et al.
Age-related decline of rat liver multicatalytic proteinase activity and protection from oxidative inactivation by heat shock protein 90
Arch. Biochem. Biophys.
(1996) - et al.
Structure of tetraubiquitin shows how multiubiquitin chains can be formed
J. Mol. Biol.
(1994) - et al.
Age related decline in chaperone mediated autophagy
J. Biol. Chem.
(2000) - et al.
The APG8/12-activating enzyme APG7 is required for proper nutrient recycling and senescence in Arabidopsis thaliana
J. Biol. Chem.
(2002) - et al.
Peroxisome turnover by micropexophagy: an autophagy-related process
Trends Cell Biol.
(2004) - et al.
Transmembrane signaling by the human insulin receptor kinase. Relationship between intramolecular beta subunit trans- and cis-autophosphorylation and substrate kinase activation
J. Biol. Chem.
(1992)
Superoxide dismutases. An adaptation to a paramagnetic gas
J. Biol. Chem.
Calorie restriction-the SIR2 connection
Cell
Age-related changes in the 20S and 26S proteasome activities in the liver of male F344 rat
Mech. Ageing Dev.
Centenarians: the older you get, the healthier you have been
Lancet
Structural basis for sorting mechanism of p62 in selective autophagy
J. Biol. Chem.
Possible involvement of proteasome inhibition in aging: implications for oxidative stress
Mech. Ageing Dev.
Selective degradation of mitochondria by mitophagy
Arch. Biochem. Biophys.
Convergence of multiple autophagy and cytoplasm to vacuole targeting components to a perivacuolar membrane compartment prior to de novo vesicle formation
J. Biol. Chem.
A role for NBR1 in autophagosomal degradation of ubiquitinated substrates
Mol. Cell
A role for NBR1 in autophagosomal degradation of ubiquitinated substrates
Mol. Cell.
Understanding the odd science of aging
Cell
A method for the isolation of longevity mutants in the nematode Caenorhabditis elegans and initial results
Mech. Ageing Dev.
A unified nomenclature for yeast autophagy-related genes
Dev. Cell
Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice
Cell
Relationship between mitochondrial superoxide and hydrogen peroxide production and longevity of mammalian species
Free Radic. Biol. Med.
Endocrine regulation of gene activity in aging animals of different genotypes
Birth Defects Orig. Artic. Ser.
Dietary self-selection can compensate an age-related decrease of rat liver 20S proteasome activity observed with standard diet
J. Gerontol. Biol. Sci.
Changes in rat liver mitochondria with aging. Lon protease-like reactivity and N (epsilon)-carboxymethyllysine accumulation in the matrix
Eur. J. Biochem.
The TOR signalling pathway controls nuclear localization of nutrient-regulated transcription factors
Nature
The role of autophagy in aging: its essential part in the anti-aging mechanism of caloric restriction
Ann. N.Y. Acad. Sci.
p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtininduced cell death
J Cell Biol
Cross linkage and the aging process
Extended longevity in mice lacking the insulin receptor in adipose tissue
Science
SirT1 regulates energy metabolism and response to caloric restriction in mice
PLOS One
Consequences of the diabetic status on the oxidant/antioxidant balance
Diab. Metab.
Autoimmunity and apoptosis: refusing to go quietly
Nat. Med.
The proteasome
Annu. Rev. Biophys. Biomol. Str.
Epidemiological and statistical characteristics of the United States elderly population
Hypothesis. Glucose as a mediator of aging
J. Am. Geriatr. Soc.
Proteolysis: from the lysosome to ubiquitin and the proteasome
Nat. Rev. Mol. Cell Biol.
Intracellular protein degradation: from a vague idea through the lysosome and the ubiquitin-proteasome system and onto human diseases and drug targeting
Cell Death Differ.
The ubiquitin-mediated proteolytic pathway: mode of action and clinical implications
J. Cell Biochem. Suppl.
Extension of life-span by loss of CHICO, a Drosophila insulin receptor substrate protein
Science
Structure and functions of the 20S and 26S proteasomes
Annu. Rev. Biochem.
A receptor for the selective uptake and degradation of proteins by lysosomes
Science
Autophagy: many paths to the same end
Mol. Cell Biochem.
Functions of lysosomes
Annu. Rev. Physiol.
The lysosome turns fifty
Nature Cell Biol
Peptide sequences that target cytosolic proteins for lysosomal proteolysis
Trends Biochem. Sci.
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