Klotho is one of numerous genes demonstrated to influence longevity in several species of laboratory animal. Like all of the other genes it influences many fundamental cellular and metabolic processes, which makes deciphering how and why it all works to affect the pace of aging a real challenge. There are probably a few core (and very complex) arrays of biological machinery that influence aging greatly enough to be easily measurable, established long ago in the deep evolutionary past, and thus shared across many different species. However influencing these mechanisms can be accomplished by altering any one of many varied genes, or changing the level of any one of many varied proteins in tissues, and all of these changes produce other effects as well. Biology likes reuse, and any one gene or protein might play a role in dozens of mechanisms.
Thus the low-level details of the progression of aging are a maze, poorly understood at present, even though the actual results in terms of differences between old tissue and young tissue are very well cataloged and understood. This is one of the reasons why attempting to produce age-slowing drugs that work through targeted metabolic manipulation is the slow, expensive road to marginal results. More than a decade of work and upwards of a billion dollars have been poured into simply trying to recreate some aspects of one well-studied metabolic alteration that increases longevity in laboratory species, the response to calorie restriction. There is little to show for it so far but more knowledge. If that same billion dollars had been put into SENS-like repair strategies, aimed at reverting the known changes in tissues that occur with aging and letting metabolism take care of itself, we'd be most of the way towards a rejuvenation toolkit demonstrated in mice by now. But no-one said the world was rational.
Here researchers speculate on the relationship between klotho and muscle metabolism, suggesting that it might shed some more light on why exactly it is that exercise improves long-term health:
Mankind has long sought means to extend longevity and counteract the effects of aging on physical functioning. Modern day scientific discoveries have made considerable strides in our biological understanding of contributing factors in the aging process. Such discoveries are critical for the development of therapeutic strategies to prevent, delay or reverse age-related declines.
Klotho is a powerful longevity protein that has been linked to the prevention of muscle atrophy, osteopenia, and cardiovascular disease. Similar anti-aging effects have also been ascribed to exercise and physical activity. While an association between muscle function and Klotho expression has been previously suggested from longitudinal cohort studies, a direct relationship between circulating Klotho and skeletal muscle has not been investigated. In this paper, we present a review of the literature and preliminary evidence that, together, suggests Klotho expression may be modulated by skeletal muscle activity.
Our pilot clinical findings performed in young and aged individuals suggest that circulating Klotho levels are upregulated in response to an acute exercise bout, but that the response may be dependent on fitness level. A similar upregulation of circulating Klotho is also observed in response to an acute exercise in young and old mice, suggesting that this may be a good model for mechanistically probing the role of physical activity on Klotho expression. Finally, we highlight overlapping signaling pathways that are modulated by both Klotho and skeletal muscle and propose potential mechanisms for cross-talk between the two. It is hoped that this review will stimulate further consideration of the relationship between skeletal muscle activity and Klotho expression, potentially leading to important insights into the well-documented systemic anti-aging effects of exercise.