Considering Klotho Delivery as a Means to Reduce Age-Related Stem Cell Decline

Today I'll point out an open access paper on the longevity-related gene klotho. Some researchers see therapies to adjust levels of the klotho protein produced from this genetic blueprint as a possible way to slow some of the effects of aging, particularly those connected to regeneration and stem cell activity. Work on this is slow-moving and painstaking, as for any similar approaches.

Yet a fairly large section of the medical research community is now devoted to at least partial and temporary restoration of tissue maintenance by stem cells in the old. A good fraction of the frailty and failure of aging results not just from direct damage such as cross-links in the extracellular matrix and broken mitochondria run amok, but also from the lack of repair of tissues, the faltering of the supply of new cells produced by stem cells in order to replace the old. Stem cell transplants are only the earliest and most direct way to try to temporarily boost regeneration and maintenance. In recent years many other possibilities have blossomed, these approaches involving the adjustment of specific biochemical signals so as to instruct native cells to return to work.

Where researchers have determined what happens to stem cell populations in the old, which is by no means a finished process given the wide range of tissue types still to be investigated fully, it seems that for the most part stem cells are neither missing nor critically impaired, but rather quiescent, simply inactive. This quiescence is thought to be an evolved response to the threat of cancer arising due to damaged DNA and cellular environments, with the present balance between activity and cancer on the one hand versus quiescence and failing organs on the other being the outcome of selection pressure for ever-longer human life spans. We are long-lived among mammals - and even primates - most likely because our intelligence and culture allowed the old to contribute to the success of their grandchildren.

So is it possible to gain meaningful benefits by ramping up a damaged engine, by signaling stem cells to get back to work without actually addressing any of the underlying cell and tissue damage that causes this evolved reaction of growing quiescence? Will this produce an excessive cancer risk, for example? It is of interest that so far there has been a surprising lack of cancer resulting from work in the laboratory and clinic, if anything. It may be that the characteristic stem cell decline with aging is not all that fine-tuned by evolution and that there is considerable wiggle room to produce therapies that can do better than today's medicine despite failing to address other important causes of degeneration. Either way, the stem cell issues ultimately need to be fixed as a part of any comprehensive toolkit of rejuvenation therapies. Damaged stem cells should be replaced or repaired, not just sent back to work.

Klotho, stem cells, and aging

Since klotho was serendipitously identified in 1997, our understanding of it as an aging suppressor has been continuously growing. Klotho protein has pleiotropic actions on many organs and tissues in mammals. However, very limited and premature data about klotho effects on stem cells are available. A better understanding of the effects of klotho on stem cells not only provides novel insights into the role of stem cells in antiaging processes but could also make a significant contribution to the advancement of regenerative medicine clinical practice.

Given that changes of functionality and a decreased number of stem cells contribute to or accelerate aging, implantation of stem cells to replenish new functional stem cells would be one means to attenuate age-associated disease by rebuilding the tissue or organ. This has been shown to be effective in preclinical and clinical trials in some diseases, including multiple sclerosis, myocardial infarction, ischemic stroke, and cancer. However, long-term side effects of stem cell implantation are not fully recognized, and should be a concern in most cases in which stem cells are permanently injected into patients. For example, recipients of genetically altered bone marrow transplants developed leukemia years after their allegedly successful transplants had cured their severe combined immunodeficiency. Despite potential side effects, recent advances in stem cell research and technology have shown promise.

On the other hand, activation or stimulation of endogenous or resident stem cells is another strategy to abate aging and age-associated disease. Current data from animal and in vitro cell-culture studies clearly demonstrated that klotho deficiency is associated with stem cell senescence and depletion. Furthermore, klotho deficiency may not only be a trigger for aging but also a pathogenic intermediate for accelerated aging and development of age-associated diseases, including Alzheimer's disease, hypertension, osteoporosis, cardiovascular disease, and chronic kidney disease (CKD). Conceivably, any therapy that restores or stimulates endogenous klotho or administration of exogenous klotho might provide a novel treatment strategy for aging and age-associated diseases.

To date, klotho gene delivery is shown to effectively rescue many phenotypes observed in klotho-deficient mice. Although gene therapy is effective in animal studies, its safety is still questionable, and clinical application is not in proximity. There are few clinical trials testing gene therapy in specific diseases. Compared to viral delivery of the klotho gene in animals, administration of exogenous klotho protein is a safer, easier, and more direct modality to restore endocrine klotho deficiency. Similarly to the use of erythropoietin or erythropoiesis-stimulating agents to correct anemia in CKD patients and insulin to maintain normal glucose metabolism in type I diabetes, the administration of exogenous klotho protein may be a viable and effective option in the near future to dwindle aging. Klotho protein can potentially reverse or retard stem cell depletion and abate age-associated pathological processes.

To date, no studies of klotho protein administration in humans have been reported. In contrast, animal studies have already provided convincing and encouraging data to support the proof of concept that soluble klotho protein administration is safe and effective. We showed that soluble klotho protein attenuates kidney damage and preserves kidney function in an ischemia-reperfusion injury model causing acute kidney injury, which is a state of acute klotho deficiency. Furthermore, klotho protein inhibited renal fibrosis in a unilateral ureteral obstruction kidney-injury model, which is also a state of low klotho expression in the kidney. Therefore, the preclinical data clearly support the therapeutic potential of soluble klotho protein for age-related disorders and klotho deficiency-associated diseases.

Thus far, animal experiments and in vitro cell-culture studies have shown the effects of soluble klotho protein on abating skin atrophy and skeletal muscle dystrophy during aging. It is anticipated that soluble klotho may play a pivotal role in regenerative medicine by preservation and activation of stem cells, particularly in heart tissue, where stem cells are very scarce or have low ability to replicate after injury. Therefore, if soluble klotho can activate stem cells or induce the replication of stem cells, klotho protein could be used as a promising therapeutic strategy for tissue repair and organ regeneration.

Comments

You say they are damaged but Irina and Michael Conboy demonstrate that rejuvenated cells are almost as good as new ones and damage was repaired upon rejuvenation. I still do not buy into this idea of revving up broken machinery you keep talking about. I agree that the stem cell pool does need replacing though or at the least topping up and that is something within our reach now.

Posted by: Steve Hill at September 15th, 2015 8:18 AM

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