Peroxisomal alterations in aging and age-related disease

Abstract Despite the myriad of peroxisomal enzymes involved in essential cellular metabolic pathways, little attention has been focused on the relationship between changes in the activities of these enzymes and the process of cellular aging. A few reports in the literature suggest the presence of an aging-associated decline in hepatic peroxisomal enzyme activities and in their response to peroxisome proliferating chemicals. The exact basis for the relationship between peroxisomal deficit, aging and death is not clear. However, an aging-related decline in peroxisomal protein synthesis, among other proteins, is expected to diminish peroxisomal capacity to metabolize very long-chain fatty acids. This effect may be manifested in an altered composition of the structure of cellular and organellar membranes. For example, it has been reported that aging causes an increase in the cholesterol/phospholipid ratio in rat liver microsomal, mitochondrial and cellular membranes ( Grinna, 1976 ; Zs-Nagy, 1979) . Phospholipids are essential for the activation of various signal transduction pathways. This includes the modulation of protein kinase C activity by membrane phospholipids ( Takai et al., 1984) . Accordingly, changes in membrane phospholipids as a result of age-related diminished peroxisomal metabolism may trigger a cascade of events and/or interrupt normal important cellular functions. Since PPARs regulate gene expression of enzymes associated with lipid homeostasis (Devchand et al., 1996) , it is feasible that age-related changes in the expression and/or activity of these receptors may be involved in aging and age-related diseases. Also, it becomes clear that altered expression and/or responsiveness of PPARs in aged subjects could potentially result in the modulation of inflammatory intensity and duration, obesity, diabetes and cancer. Another connection between peroxisomal senescence and cellular aging is exemplified by the fact that aging-associated changes in membrane phospholipid composition is also accompanied by an increase in Na, K-ATPase activity and intracellular potassium content (Zs-Nagy, 1979) . Increased intracellular ion concentrations are postulated to reduce the activity of the whole translational machinery, increase aggregation of macromolecules, retarding all enzymatic catalysis ( Hey et al., 1976 ; Zs-Nagy, 1979 ), and to interfere with mitotic activity (Cone, 1971) . This, in turn, may initiate a vicious cycle leading to further diminution of peroxisomal metabolism. Peroxisomes grow by the posttranslational incorporation of new content and membrane proteins into preexisting peroxisomes which then divide to form daughter peroxisomes in a dynamic “fission” process (Lazarow and Fujiki, 1985) . The cloning and identification of PPARγ as a nuclear receptor that can regulate important facets of energy balance has offered new opportunities to understand several key metabolic processes. This form of PPAR is considered a promising candidate gene for involvement in several human disorders including obesity and type 2 diabetes mellitus (Yen, et al., 1997) . Although adipose tissue has been recognized as a principal site of expression of PPARγ, this receptor is also expressed, albeit at lower levels, in many other tissues and cell types (Mueller et al., 1998) . The apparent contradiction between the need to develop PPARγ agonists to treat insulin resistance and the need to develop PPARγ antagonists to treat obesity will require further understanding of the potential multiple roles of these receptors and the intricate interrelationships between various metabolic pathways. Although the existence of a causal relationship between peroxisomal senescence and cellular aging has not been established, the importance of these organelles to normal cell functions and cellular survival makes the investigation of their role in aging and aging-related diseases an urgent task. The impact of aging on extracellular matrix, growth factors, cytokines and nonparenchymal cells, among other factors which are known to influence peroxisomal metabolism, will be of utmost importance to our understanding of the relationship between aging and peroxisomal metabolism. Alterations in these factors, with aging, may explain aging-related effects on peroxisomal population and enzyme activities and their role in aging-related disease and death.