AMPK activation—protean potential for boosting healthspan

Abstract

AMP-activated kinase (AMPK) is activated when the cellular (AMP+ADP)/ATP ratio rises; it therefore serves as a detector of cellular "fuel deficiency." AMPK activation is suspected to mediate some of the health-protective effects of long-term calorie restriction. Several drugs and nutraceuticals which slightly and safely impede the efficiency of mitochondrial ATP g e n e r a t i o n -m o s t n o t a b l y m e t f o r m i n a n d berberine-can be employed as clinical AMPK activators and, hence, may have potential as calorie restriction mimetics for extending healthspan. Indeed, current evidence indicates that AMPK activators may reduce risk for atherosclerosis, heart attack, and stroke; help to prevent ventricular hypertrophy and manage congestive failure; ameliorate metabolic syndrome, reduce risk for type 2 diabetes, and aid glycemic control in diabetics; reduce risk for weight gain; decrease risk for a number of common cancers while improving prognosis in cancer therapy; decrease risk for dementia and possibly other neurodegenerative disorders; help to preserve the proper structure of bone and cartilage; and possibly aid in the prevention and control of autoimmunity. While metformin and berberine appear to have the greatest utility as clinical AMPK activators-as reflected by their efficacy in diabetes management-regular ingestion of vinegar, as well as moderate alcohol consumption, may also achieve a modest degree of healthprotective AMPK activation. The activation of AMPK achievable with any of these measures may be potentiated by clinical doses of the drug salicylate, which can bind to AMPK and activate it allosterically.

Pharmacological Strategies to Retard Cardiovascular Aging

“…180,181 Aspirin, also known as acetylsalicylic acid, is used at low doses as an antiplatelet drug in the prevention of vascular ischemic events and has been shown to increase lifespan in genetically heterogeneous male mice. 182 This nonsteroidal anti-inflammatory drug activates AMPK 183 to decrease the expression of inducible nitric oxide synthase (iNOS) and Cox-2 184 and, therefore, lowers inflammation and oxidative stress. Similar protective effects have been observed with berberine.…”

Neurohormetic phytochemicals: An evolutionary–bioenergetic perspective

“…AMPK is involved in the regulation of energy metabolic homeostasis, serving as a detector of cellular fuel deficiency that is activated when the cellular (AMP+ADP)/ATP ratio rises (Hardie, 2011; McCarty, 2014). There is a positive feedback loop interaction between AMPK and SIRT1, whereby the activation of AMPK increases the intracellular level of NAD+, thus stimulating the activity of SIRT1.…”

“…Evidence suggests that AMPK activators can improve health (McCarty, 2014). Park et al (2012) reported that metabolic effects of resveratrol arise from inhibition of cAMP-degrading phosphodiesterases.…”

Impacts of metformin and aspirin on life history features and longevity of crickets: trade-offs versus cost-free life extension?

“…AMPK also downregulates NFκB via phosphorylation of Iκκβ, thereby reducing NAD(P)H oxidase activity (McCarty 2014). Besides regulating stress resistance, salicylic acid can act as an antioxidant and chelator to inhibit iron-mediated generation of hydroxyl radical (Yang et al 2004).…”

“…Aspirin regulates AMPK via direct phosphorylation McCarty 2014), whereas metformin indirectly activates AMPK by reducing mitochondrial complex I and energy production (El Mir et al 2000;Owen et al 2000;Viollet et al 2012). Martin-Montalvo et al (2013) suggest, however, that mice may adapt to this impact of metformin.…”