Fight Aging!

Calorie restriction has a sizable effect on health and life span in the short-lived species used in scientific studies of aging, and produces sweeping changes in the regulation of cellular biochemistry. The combination of these two points has ensured that near all approaches discovered to slow aging to date operate on aspects of cellular biochemistry that are involved in the calorie restriction response. In the course of producing a body of data in numerous species including worms, flies, and mice, it has become clear that short-lived species are much more responsive to these interventions than is the case for long-lived species. There is an argument to be made that most of the research and development in the field of aging is looking in the wrong places for approaches that will work well in long-lived mammals such as our own species. That doesn't mean that the field as a whole is incapable of producing sizable gains in life span, however. It would be premature to draw that conclusion.

Well-documented anti-aging treatments across species of increasing complexity include drugs such as rapamycin, resveratrol, spermidine, chloroquine, and even medications historically employed for treating different diseases, like metformin, which is used in the management of type 2 diabetes. The decreasing magnitude of the positive effect with increasing species complexity in anti-aging treatments is obvious. Thus, we noted the positive effects of metformin decreased from 50% in S. cerevisiae to negligible (if any) effects in humans. Similarly, the effects of resveratrol decreased almost linearly from 70% in S. cerevisiae to 41% in Drosophila, to 30% in C. elegans, to 26% in rodents. The impact of rapamycin on lifespan across species decreased progressively, from 57% in S. cerevisiae to approximately 29% in Drosophila, further declining to 25% in C. elegans, and ultimately reaching 13% in rodents.

The limited translatability between species of increasing complexity can be explained by a number of factors. The effectiveness or significance of the targeted molecule from a pathway might differ in various metabolic scenarios. For example, the anti-aging mechanisms of resveratrol primarily involve ameliorating oxidative stress by scavenging reactive oxygen species (ROS). However, ROS play a more significant role in flying species like Drosophila than in mammals, which may possess additional mechanisms to counteract ROS. Indeed, recent research has revealed a more complex and beneficial role of ROS in regulating metabolism, development, and lifespan.

Second, the weight of targeted signaling pathways differs for a species' general metabolism. Therefore, single mutations that reduce insulin/IGF-1 signaling can significantly increase the lifespan of simple organisms such as C. elegans and D. melanogaster. However, the increased complexity of the pathway, attributed to additional regulators like insulin and growth hormone, has made it challenging to distinguish the roles of each key component in mammalian longevity.

Third, redundancy in pathways is a widespread phenomenon in species of increasing complexity, observed across all forms of life. It has developed as a safeguard against disturbances that might otherwise interfere with essential processes, such as mutations or shifts in the environment. Thus, blocking one pathway does not necessarily impede the cellular or organismal process.

Fourth, as we make progress into research on anti-aging therapies, the challenges posed by the increasing complexity of species remind us that, much like many aspects of biology and medicine, there exists a law of diminishing returns. While the initial interventions may yield significant and noticeable impacts, the subsequent benefits might be less pronounced with the addition of more layers of complexity and control.

Link: https://doi.org/10.1111/acel.14208