Delivering Klotho to Old Mice Partially Reverses Loss of Muscle Regenerative Capacity

Klotho is one of the better known longevity-associated genes. More klotho improves function and slows measures of aging in mice, and there is suggestive evidence for the same to be true to some degree in humans. The effect on life span is likely to be smaller in our comparatively long-lived species, unfortunately. This is true of all of the approaches to slowing aging for which there is data in both mice and humans to directly compare. Changes to the operation of metabolism that influence the pace of aging are subject to a long history of evolutionary pressures that lead to much greater plasticity of lifespan in response to environmental circumstances in short-lived species. Consider seasonal famines for example; a season is a sizable fraction of a mouse life span, but not of a human life span, and so only the mouse evolves the ability to live much longer when subject to stresses of this nature.

Much of the recent work on klotho has focused on its positive influence on the function of the brain. Delivering klotho improves cognitive function in both young and old animals, and thus this approach to therapy isn't just a case of producing a tool to mitigate some of the mental declines of aging, even though it is very much the case that levels of klotho diminish in later life. Klotho therapies, once developed, might be an enhancement that could benefit all people.

Klotho doesn't just act in the brain, however. As the research noted here makes clear, klotho also plays an important role in the regeneration of muscle tissue. This is the result of long years of investigation into how klotho interacts with the rest of cellular biochemistry in muscles; it is a complex business. The open access paper below outlines evidence to suggest that mitochondrial function is the critical mechanism by which klotho provides benefits. Mitochondria are the power plants of the cell, providing energy stores needed for cellular function. Loss of mitochondrial function is implicated in numerous aspects of aging, particularly in energy-hungry brain and muscle tissues. So it may well be that a sizable fraction of klotho's benefits in the brain are also mediated by greater mitochondrial function.

'Longevity Protein' Rejuvenates Muscle Healing in Old Mice

One of the downsides to getting older is that skeletal muscle loses its ability to heal after injury. New research implicates Klotho, both as culprit and therapeutic target. In young animals, Klotho expression soars after a muscle injury, whereas in old animals, it remains flat. By raising Klotho levels in old animals, or by mitigating downstream effects of Klotho deficiency, the researchers could restore muscle regeneration after injury. "We found that we were able to rescue, at least in part, the regenerative defect of aged skeletal muscle. We saw functional levels of muscle regeneration in old animals that paralleled those of their young counterparts, suggesting that this could potentially be a therapeutic option down the road."

Suspecting that Klotho acts through mitochondria dysfunction, the researchers gave Klotho-deficient animals a mitochondria-targeting drug called SS-31, which currently is in phase III clinical trials. Treated animals grew more new muscle tissue at the site of injury compared to untreated controls, and their strength after recovery rivaled that of genetically normal mice. Similarly, injecting Klotho into older animals a few days after injury resulted in greater muscle mass and better functional recovery than their saline-treated counterparts. Normal, healthy mice did not benefit from SS-31 after injury. Clinically, these findings could translate to older adults who either sustained a muscle injury or underwent muscle-damaging surgery. Giving them Klotho at the appropriate timepoint could boost their muscle regeneration and lead to a more complete recovery.

Age-related declines in α-Klotho drive progenitor cell mitochondrial dysfunction and impaired muscle regeneration

In this study, we tested the hypothesis that age-related declines in α-Klotho drive dysfunctional muscle progenitor cell (MPC) mitochondrial bioenergetics, ultimately resulting in an impaired tissue regeneration. Our findings demonstrate that young skeletal muscle displays a robust increase in local α-Klotho expression following an acute muscle injury with transient demethylation of the Klotho promoter. However, aged muscle displays no change in Klotho promoter methylation and no increase in α-Klotho expression following injury.

Levels of α-Klotho in MPCs derived from aged mice are decreased relative to those of young animals, and genetic knockdown of α-Klotho in young MPCs confers an aged phenotype with pathogenic mitochondrial ultrastructure, decreased mitochondrial bioenergetics, mitochondrial DNA damage, and increased senescence. Further supporting a role for α-Klotho in skeletal muscle vitality, mice heterozygously deficient for Klotho (Kl+/-) have impaired MPC bioenergetics that is consistent with a defective regenerative response following injury, but the regenerative defect of Kl+/- mice is rescued at the cellular and organismal level when mitochondrial ultrastructure is restored through treatment with the mitochondria-targeted peptide, SS-31.

Finally, we demonstrate that systemic delivery of exogenous α-Klotho rejuvenates MPC bioenergetics and enhances functional myofiber regeneration in aged animals in a temporally dependent manner. Together, these findings reveal a role for α-Klotho in the regulation of MPC mitochondrial function and skeletal muscle regenerative capacity.