Linking Peroxiredoxin and Vacuolar-ATPase Functions in Calorie Restriction-Mediated Life Span Extension

Abstract

Calorie restriction (CR) is an intervention extending the life spans of many organisms. The mechanisms underlying CR-dependent retardation of aging are still poorly understood. Despite mechanisms involving conserved nutrient signaling pathways proposed, few target processes that can account for CR-mediated longevity have so far been identified. Recently, both peroxiredoxins and vacuolar-ATPases were reported to control CR-mediated retardation of aging downstream of conserved nutrient signaling pathways. In this review, we focus on peroxiredoxin-mediated stress-defence and vacuolar-ATPase regulated acidification and pinpoint common denominators between the two mechanisms proposed for how CR extends life span. Both the activities of peroxiredoxins and vacuolar-ATPases are stimulated upon CR through reduced activities in conserved nutrient signaling pathways and both seem to stimulate cellular resistance to peroxide-stress. However, whereas vacuolar-ATPases have recently been suggested to control both Ras-cAMP-PKA- and TORC1-mediated nutrient signaling, neither the physiological benefits of a proposed role for peroxiredoxins in H2O2-signaling nor downstream targets regulated are known. Both peroxiredoxins and vacuolar-ATPases do, however, impinge on mitochondrial iron-metabolism and further characterization of their impact on iron homeostasis and peroxide-resistance might therefore increase our understanding of the beneficial effects of CR on aging and age-related diseases.

Light-sensing via hydrogen peroxide and a peroxiredoxin

“…The exquisite sensitivity of peroxiredoxin catalytic cysteines to H 2 O 2 makes them ideally suited both as receptors to relay light-induced H 2 O 2 signals, as well H 2 O 2 scavengers to terminate them52. By identifying a peroxiredoxin as a light-receptor of cAMP-PKA, which constitutes a pleiotropic nutrient-responsive pathway regulating, for example, core circadian clock mechanisms53 and ageing15, our data contribute to the understanding of the roles of light, H 2 O 2 and peroxiredoxins in the control of endogenous rhythms in general. The data also suggest that peroxiredoxin hyperoxidation and reactivation play a critical role in modulating endogenous rhythmicity by turning off and on H 2 O 2 -mediated signal transduction, respectively.…”

“…Typical 2-Cys peroxiredoxins are enzymes that reduce hydrogen peroxide (H 2 O 2 ) via two catalytic cysteines and thioredoxin acting as the hydrogen donor1516. During catalysis, a small proportion of the primary catalytic (peroxidatic) cysteine becomes hyperoxidized to the sulfinylated (Cys–SO 2 H) form, which inactivates the enzyme1718.…”

“…During catalysis, a small proportion of the primary catalytic (peroxidatic) cysteine becomes hyperoxidized to the sulfinylated (Cys–SO 2 H) form, which inactivates the enzyme1718. Peroxiredoxins have received increased attention because of their functions in suppressing malignant tumours19, in keeping the genome free of mutations20 and as conserved executors of the ability of caloric restriction to slow down the rate of ageing151621222324. In addition, peroxiredoxin hyperoxidation was shown to sustain transcription-independent circadian rhythms in organisms from the three kingdoms of life1252627.…”

Amyloid precursor protein and endosomal‐lysosomal dysfunction in Alzheimer's disease: inseparable partners in a multifactorial disease

“…Cellular aging, the sine qua non for AD and other late‐onset diseases, critically involves declines of autophagic flux and lysosomal function. Recent evidence more directly implicates the decline of lysosomal acidification in the reduction of longevity (173), reversal of which has been achieved in yeast by overexpressing v‐ATPase components (173, 174) or restricting calories or methionine (173, 175).…”

Disorders of lysosomal acidification—The emerging role of v-ATPase in aging and neurodegenerative disease

“…Increased vacuolar pH early in life contributed to age-related mitochondrial dysfunction and a shortened lifespan in this study and vacuolar acidity further declined with aging. Vacuolar acidification seems also to be critical in mediating lifespan-extending effects of caloric restriction (Hughes and Gottschling, 2012; Molin and Demir, 2014) and methionine restriction (Ruckenstuhl et al, 2014). Additionally, overexpression of v-ATPase components promotes increased lifespan in yeast models (Hughes and Gottschling, 2012; Ruckenstuhl et al, 2014).…”