Angiotensin II blockade: how its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition.
Caloric restriction (CR), renin angiotensin system blockade (RAS-bl), and rapamycin-mediated mechanistic target of rapamycin (mTOR) inhibition increase survival and retard aging across species. Previously, we have summarized CR and RAS-bl's converging effects, and the mitochondrial function changes associated with their physiological benefits. mTOR inhibition and enhanced sirtuin and KLOTHO signaling contribute to the benefits of CR in aging. mTORC1/mTORC2 complexes contribute to cell growth and metabolic regulation. Prolonged mTORC1 activation may lead to age-related disease progression; thus, rapamycin-mediated mTOR inhibition and CR may extend lifespan and retard aging through mTORC1 interference. Sirtuins by deacetylating histone and transcription-related proteins modulate signaling and survival pathways and mitochondrial functioning. CR regulates several mammalian sirtuins favoring their role in aging regulation. KLOTHO/fibroblast growth factor 23 (FGF23) contribute to control Ca(2+), phosphate, and vitamin D metabolism, and their dysregulation may participate in age-related disease. Here we review how mTOR inhibition extends lifespan, how KLOTHO functions as an aging suppressor, how sirtuins mediate longevity, how vitamin D loss may contribute to age-related disease, and how they relate to mitochondrial function. Also, we discuss how RAS-bl downregulates mTOR and upregulates KLOTHO, sirtuin, and vitamin D receptor expression, suggesting that at least some of RAS-bl benefits in aging are mediated through the modulation of mTOR, KLOTHO, and sirtuin expression and vitamin D signaling, paralleling CR actions in age retardation. Concluding, the available evidence endorses the idea that RAS-bl is among the interventions that may turn out to provide relief to the spreading issue of age-associated chronic disease.
Center of Hypertension, Cardiology Department, Austral University Hospital, Derqui, Argentina; School of Biomedical Sciences, Austral University, Buenos Aires, Argentina; and elenacavanagh@yahoo.com.ar.
Elena M V
EM
de Cavanagh
Center of Hypertension, Cardiology Department, Austral University Hospital, Derqui, Argentina; School of Biomedical Sciences, Austral University, Buenos Aires, Argentina; and.
Felipe
F
Inserra
Department of Physiology and Pharmacology, Ponce School of Medicine, Ponce, Puerto Rico.
León
L
Ferder
D000375:Aging / Q000378:metabolism*; D000804:Angiotensin II / Q000378:metabolism*; D031204:Caloric Restriction; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism; D005966:Glucuronidase / Q000378:metabolism; D006801:Humans; D000090265:Klotho Proteins; D008136:Longevity; D000076222:Mechanistic Target of Rapamycin Complex 1; D008928:Mitochondria / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000378:metabolism; D012084:Renin-Angiotensin System; D015398:Signal Transduction; D037761:Sirtuins / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014807:Vitamin D / Q000378:metabolism
C000717427:FGF23 protein, human; D046912:Multiprotein Complexes; D018167:Receptors, Calcitriol; D000804:Angiotensin II; D014807:Vitamin D; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D005966:Glucuronidase; D000090265:Klotho Proteins; D037761:Sirtuins
caloric restriction; mechanistic target of rapamycin; renin-angiotensin system; vitamin D