AMPK at the nexus of energetics and aging

Abstract

When energy supply is low, organisms respond by slowing aging and increasing resistance to diverse age-related pathologies. Targeting the mechanisms underpinning this response may therefore treat multiple disorders through a single intervention. Here, we discuss AMP-activated protein kinase (AMPK) as an integrator and mediator of several pathways and processes linking energetics to longevity. Activated by low energy, AMPK is both prolongevity and druggable, but its role in some pathologies may not be beneficial. As such, activating AMPK may modulate multiple longevity pathways to promote healthy aging, but unlocking its full potential may require selective targeting toward substrates involved in longevity assurance.

Figure 1. Co-morbidities and Age-related Pathologies

Each bar represents pathological state of an individual patient from birth to death. Green equals no pathology. As each chronic disease (CD) presents, decreases in health is portrayed by increased ‘heat’ of color. A. Patients over 65 rarely have one age-related pathology in isolation, but instead have multiple comorbidities that develop concurrently. B. Therefore, eradicating one disease (CD1) in it entirety will not dramatically increase disease free life. C. Targeting age-related frailty and systemic disease risk might alternatively delay the onset of multiple pathologies and greatly improve healthy aging.

Figure 2. AMPK Signaling and Aging Pathways

AMPK sits upstream of multiple signal transduction pathways known to modulate the aging process. Lines represent direct signaling effects. Color of line reflects effect on target – green equals activating, red equals inhibiting. Color of modification equals effect of modification – green equals activating, red equals inhibiting. Arrow signifies adds modification, T bar signifies removes modification. Therefore, for example, removing an inhibitory modification generates a green T bar, as the effect on the target is activation. Orange factors are anti-longevity, blue are pro-longevity.

Figure 3. Physiological effects of AMPK

Schematic of selected physiological effects on AMPK and the intermediate mediators. Arrows signify activation, T bars signify suppression. Green signifies pro-longevity, red signifies anti-longevity.