The authors of this open access papers discuss the prominent role of cell signaling in the better known classes of intervention that have been shown to slow aging in worms, flies, and mice. The body is a network in which cells in one tissue influence the behavior of cells in other tissues via the signal molecules and vesicles that they secrete into the circulatory system. This leads to a focus on mimicking these signals, such as in the production of calorie restriction mimetics and exercise mimetics. As an approach to extending healthy life span, this seems likely to be bounded in effectiveness by the present natural variability of life span in response to environment and circumstance. Many of us consider this to be a case of aiming too low, a poor strategy in comparison to the goal of periodic repair of the underlying damage that causes aging.
The benefits of discovering therapeutics that target aging are many, including (1) decreasing the financial burden on our strained healthcare system, (2) increasing the amount of time older adults live free of chronic diseases (often denoted as healthspan), and (3) potentially increasing maximum human lifespan. Organismal lifespan was first presented as a genetically modifiable trait by groundbreaking publications describing the effects of the FOXO transcription factor DAF-16 on longevity in Caenorhabditis elegans. Although modifying genes or substantially changing environments is not plausible in humans, it is feasible to find anti-aging therapeutics that mimic environmental cues or genetic signaling environments.
Deciphering how cells relay information to one another remains one of the foundational discoveries in biology. This concept, that cells can relay critical information to other cells in response to an initial signaling cue, allows for genes expressed in one cell or tissue to affect the physiology of other cells and tissues. This ability of genes to affect processes outside of the cells they are expressed in is often referred to as cell non-autonomous action or signaling.
More recently, high-profile publications from multiple labs have shown that many signaling pathways reported to improve longevity (e.g. mitochondrial stress, insulin-like signaling, heat shock, and the hypoxic response) act through cell non-autonomous signaling mechanisms. These pathways originate in sensory cells, often neurons, that signal to peripheral tissues and promote survival during the presence of stress. Importantly, this activation of stress response pathways, either through genetic modification or exposure to environmental stress, is often sufficient to improve health and longevity. Additionally, genetic modification of these pathways can often target the aging process while sparing growth/development/reproduction effects that are often consequences of environmental stress. Understanding how cell non-autonomous signaling influences longevity is a relatively recent concept in aging research and presents a novel opportunity to discover pharmacological interventions that modulate signaling to increase healthspan and longevity.
With the establishment of cell non-autonomous regulation of aging in multiple pathways and organisms, there is immense therapeutic potential for this area going forward. Most therapeutics logically target the tissues where physiological change is important, while understanding signaling networks provides a unique opportunity to use the natural signaling network to 'trick' key tissues into improving long-term health. This will not necessarily be easy, as targeting neural circuits using broad drugs (e.g. SSRIs) often have pleiotropic effects, but the better we understand the signaling networks the more specifically we could, in theory, mimic the signals. Using a signaling approach to anti-aging therapeutics would allow for induction of hormetic effects without the need for an acute stress, and has great potential to mimic well-established longevity interventions such as dietary restriction.