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 pro-longevity 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 towards substrates involved in longevity-assurance.

Summary Mitochondrial network remodeling between fused and fragmented states facilitates mitophagy, interaction with other organelles and metabolic flexibility. Aging is associated with a loss of mitochondrial network homeostasis, but cellular processes causally linking these changes to organismal senescence remain unclear. Here, we show that AMP-activated protein kinase (AMPK) and dietary restriction (DR) promote longevity in C. elegans via maintaining mitochondrial network homeostasis and functional coordination with peroxisomes to increase fatty acid oxidation (FAO). Inhibiting fusion or fission specifically blocks AMPK- and DR-mediated longevity. Strikingly however, preserving mitochondrial network homeostasis during aging by co-inhibition of fusion and fission is sufficient itself to increase lifespan, while dynamic network remodeling is required for intermittent fasting-mediated longevity. Finally, we show that increasing lifespan via maintaining mitochondrial network homeostasis requires FAO and peroxisomal function. Together these data demonstrate that mechanisms that promote mitochondrial homeostasis and plasticity can be targeted to promote healthy aging.

SUMMARY Mitochondria undergo architectural/functional changes in response to metabolic inputs. How this process is regulated in physiological feeding/fasting states remains unclear. Here we show that mitochondrial dynamics (notably fission and mitophagy) and biogenesis are transcriptional targets of the circadian regulator Bmal1 in mouse liver and exhibit a metabolic rhythm in sync with diurnal bioenergetic demands. Bmal1 loss-of-function causes swollen mitochondria incapable of adapting to different nutrient conditions accompanied by diminished respiration and elevated oxidative stress. Consequently, liver-specific Bmal1 knockout (LBmal1KO) mice accumulate oxidative damage and develop hepatic insulin resistance. Restoration of hepatic Bmal1 activities in high fat fed mice improves metabolic outcomes, whereas expression of Fis1, a fission protein that promotes quality control rescues morphological/metabolic defects of LBmal1KO mitochondria. Interestingly, Bmal1 homologue AHA-1 in C. elegans retains the ability to modulate oxidative metabolism and lifespan despite lacking circadian regulation. These results suggest clock genes are evolutionarily conserved energetics regulators.

SUMMARY Low energy states delay aging in multiple species, yet mechanisms coordinating energetics and longevity across tissues remain poorly defined. The conserved energy sensor AMP-activated protein kinase (AMPK) and its corresponding phosphatase calcineurin modulate longevity via the CREB regulated transcriptional coactivator (CRTC)-1 in C. elegans. We show that CRTC-1 specifically uncouples AMPK/calcineurin-mediated effects on lifespan from pleiotropic side effects by reprogramming mitochondrial and metabolic function. This pro-longevity metabolic state is regulated cell-nonautonomously by CRTC-1 in the nervous system. Neuronal CRTC-1/CREB regulates peripheral metabolism antagonistically with the functional PPARα ortholog, NHR-49, drives mitochondrial fragmentation in distal tissues, and suppresses the effects of AMPK on systemic mitochondrial metabolism and longevity via a cell-nonautonomous catecholamine signal. These results demonstrate that while both local and distal mechanisms combine to modulate aging, distal regulation overrides local contribution. Targeting central perception of energetic state is therefore a potential strategy to promote healthy aging.

MicroRNAs (miRNAs) are highly conserved small RNAs that act as translational regulators of gene expression, exerting their influence by selectively targeting mRNAs bearing complementary sequence elements. These RNAs function in diverse aspects of animal development and physiology. Because of an ability to act as rapid responders at the level of translation, miRNAs may also influence stress response. In this study, we show that the miR-8 family of miRNAs regulates osmoregulation in zebrafish embryos. Ionocytes, which are a specialized cell type scattered throughout the epidermis, are responsible for pH and ion homeostasis during early development before gill formation. The highly conserved miR-8 family is expressed in ionocytes and enables precise control of ion transport by modulating the expression of Nherf1, which is a regulator of apical trafficking of transmembrane ion transporters. Ultimately, disruption of miR-8 family member function leads to an inability to respond to osmotic stress and blocks the ability to properly traffic and/or cluster transmembrane glycoproteins at the apical surface of ionocytes.