Metabolic Communication and Healthy Aging: Where Should We Focus Our Energy?

Abstract

Aging is associated with a loss of metabolic homeostasis and plasticity, which is causally linked to multiple age-onset pathologies. The majority of the interventions-genetic, dietary, and pharmacological-that have been found to slow aging and protect against age-related disease in various organisms do so by targeting central metabolic pathways. However, targeting metabolic pathways chronically and ubiquitously makes it difficult to define the downstream effects responsible for lifespan extension and often results in negative effects on growth and health, limiting therapeutic potential. Insight into how metabolic signals are relayed between tissues, cells, and organelles opens up new avenues to target metabolic regulators locally rather than globally for healthy aging. In this review, we discuss the pro-longevity effects of targeting metabolic pathways in specific tissues and how these interventions communicate with distal cells to modulate aging. These studies may be crucial in designing interventions that promote longevity without negative health consequences.

Keywords: AMPK; NAD+; aging; extracellular vesicles; insulin signaling; mTOR; metabolism; microRNA; sirtuins; tissue-specificity.

Figure 1.. Crosstalk between metabolic pathways and the tissues in which they are implicated in aging regulation.

The central nutrient-sensing metabolic pathways in a cell participate in crosstalk with each other through many nodes. This figure depicts a simplified version of the IIS, mTOR, AMPK, and sirtuin signaling pathways focusing primarily on the pathway components mentioned in this review. The interactions shown here represent post-translational modifications (i.e. protein phosphorylation); gray arrows indicate activation while red lines indicate inhibition. A colored circle around a protein indicates that at least one study - in C. elegans, Drosophila, or mouse - found that manipulating the protein in a single tissue altered lifespan of the organism. (*Note that the intestine of C. elegans is the main metabolic tissue, serving as a proxy for mammalian intestine, fat, and liver.)

Figure 2.. Tissues where modulation of IIS pathway components extends lifespan.

There is a striking agreement between invertebrate and mammalian studies in that the insulin and IGF-1 receptors regulate aging primarily from the brain while the downstream effectors primarily regulate aging from peripheral tissues. In C. elegans, age-1 and daf-2 regulate longevity in the neurons (Wolkow et al., 2000) while daf-16 most strongly regulates longevity in the intestine (Libina et al., 2003). In D. melanogaster, extended lifespan can be achieved by expressing a dominant negative form of the insulin receptor (InR) in the brain (Ismail et al., 2015), overexpression of dFOXO or Pten in the muscles (Demontis and Perrimon, 2010), or overexpression dFOXO in the fat body (Giannakou et al., 2004; Hwangbo et al., 2004), although these lines may have had leaky expression in the gut (Poirier et al., 2008). Mouse lifespan can be extended by brain-specific knockout of Irs2 (Taguchi et al., 2007), brain-specific knockout of IGF1R (Kappeler et al., 2008) and fat-specific knockout of Insr (Blüher et al., 2003).

Figure 3.. Neuronal raga-1 modulates lifespan through cell-nonautonomous neuronal signals.

Loss of RAGA-1 in C. elegans extends lifespan but decreases growth. raga-1 deletion in these animals specifically requires fused intestinal mitochondria to promote longevity. This lifespan extension of raga-1 null animals is suppressed by neuron-specific rescue of raga-1, which drives mitochondrial fission in peripheral tissues non-cell autonomously through neuronal signals to modulate lifespan. These animals with neuronal raga-1 rescue show lifespan similar to wild-type (WT) animals but continue to exhibit decreased growth showing that TORC1 pathway can be modulated in specific tissues to uncouple longevity and growth (Zhang et al., 2019).