Nutritional Regulation of Autophagy and Aging
Aging may be defined as a post-maturational deterioration process of tissues and organs due to accumulation of miss functioning cellular components. A growing number of evidence indicates a strict casualty between the reduction of autophagic functionality and aging. An autophagy relation has been established with aged onset neurodegeneration, cancer and lysosomal disorder. Autophagy, which means “self eating”, is fundamentally a physiological process of degradation, and plays an indispensable role in cell restructuring, turnover of cellular proteins, and other macromolecules and intracellular organelles like effete mitochondria (Mortimore, G.E. et al., In Biology of the Lysosome, 27, 93-135, ’96; Klionsky, D.J. and Emr, S.D., Science, 290, 1717-1721, ’00). Thus, autophagy is a cell survival mechanism. It has been shown that autophagy declines with increasing age and determines cells and individual life span.
Considering autophagy regulators, the role of nutrients and hormones, is of particular significance towards the functional loss of autophagy linking with aging (Cuervo, A.M. et al., Autophagy, 01, 131-140, ’05). Recently, an approach to prevent the cellular aging by nutritional modulation of autophagy is focused by improving the knowledge of its mechanism in mammals (Kadowaki, M. et al., Mol. Aspects Med., 27, 426-443, ’06). Understanding the role of nutrition in slowing and modulating the aging process is important.
Considering autophagy regulators, the role of nutrients and hormones, is of particular significance towards the functional loss of autophagy linking with aging (Cuervo, A.M. et al., Autophagy, 01, 131-140, ’05). Recently, an approach to prevent the cellular aging by nutritional modulation of autophagy is focused by improving the knowledge of its mechanism in mammals (Kadowaki, M. et al., Mol. Aspects Med., 27, 426-443, ’06). Understanding the role of nutrition in slowing and modulating the aging process is important.
Regulatory Mechanism of Autophagy
A number of external stimuli like, starvation, hormones and nutrients, e.g., amino acids, vitamins, antioxidants, etc., are able to modulate the autophagic response. Various regulatory mechanisms working at upstream of autophagic machinery have been identified. The positive regulators of autophagy include AMPK and class III PI3K, whereas the negative regulators of autophagy include class I PI3K, AKT, Bcl-2 and mTOR. Amino acids are all known to be a prime negative regulators of autophagy and control autophagosome formation without hormonal assistance.
Molecular Machinery of Autophagy
To-date more than 30 Atg genes have been identified in yeast and many of them have orthologue in mammalian cells (Rubinsztein, D.C. et al., Nat. Rev. Drug Dicov., 6, 304-312, ’07). More than three decades after initial description of autophagy by de Duve, LC3 (mammalian homologue of yeast Atg8) is the first specific molecular marker protein and genetic tools to elucidate the mechanisms and function of autophagy. Though Atg5-Atg12 complex has quite important role in the nucleation step, but has no regulatory function on autophagy, whereas only LC3 (Atg8) can critically control the regulation of autophagy among all the Atgs. In our recent studies on LC3 characterization, we demonstrated a new soluble form of LC3-IIs besides soluble LC3-I in cytosol and LC3-IIm in the membrane fraction. Moreover, we established a sensitive and quantitative method of autophagy, termed cytosolic LC3 ratio, showing highly correlated with total proteolytic flux (Karim et al., Autophagy, 3(6), 553-560, ’07). Our newly established LC3 index could successfully monitor autophagy. So, this index must be a strong tool of physiological and nutritional study of autophagy.
Molecular Machinery of Autophagy
To-date more than 30 Atg genes have been identified in yeast and many of them have orthologue in mammalian cells (Rubinsztein, D.C. et al., Nat. Rev. Drug Dicov., 6, 304-312, ’07). More than three decades after initial description of autophagy by de Duve, LC3 (mammalian homologue of yeast Atg8) is the first specific molecular marker protein and genetic tools to elucidate the mechanisms and function of autophagy. Though Atg5-Atg12 complex has quite important role in the nucleation step, but has no regulatory function on autophagy, whereas only LC3 (Atg8) can critically control the regulation of autophagy among all the Atgs. In our recent studies on LC3 characterization, we demonstrated a new soluble form of LC3-IIs besides soluble LC3-I in cytosol and LC3-IIm in the membrane fraction. Moreover, we established a sensitive and quantitative method of autophagy, termed cytosolic LC3 ratio, showing highly correlated with total proteolytic flux (Karim et al., Autophagy, 3(6), 553-560, ’07). Our newly established LC3 index could successfully monitor autophagy. So, this index must be a strong tool of physiological and nutritional study of autophagy.