By Reason | 13 April 2023
There are a great many genes that one might target with gene therapies to treat aspects of aging. The review here is quite narrow in scope, and only looks at a few approaches to gene therapy, and a few of the genes that might be targeted, those that have arguably received more attention in this context and are either the subjects of small clinical trials or might be entering trials in the near future. It even omits follistatin and myostatin in favor of telomerase, klotho, VEGF, and APOE. The latter is probably not all that interesting as a target, but it is very well researched as a result of the strong focus on funding Alzheimer’s disease programs over the past few decades.
— 🥼Agingdoc1⭐MD, PhD 🔔 (@agingdoc1) April 4, 2023
The telomerase reverse transcriptase (TERT) gene encodes the rate-limiting catalytic TERT protein, a subunit of telomerase. Studies on telomeres and telomerase have been conducted since the start of research on aging. Many studies have shown that defects in telomeres or telomerase exert a substantial influence on the development of aging-related diseases. Some in vivo experiments have already reported that TERT gene therapy exhibits exciting efficacy for treating diverse diseases. Researchers tentatively introduced AAV-mouse Tert into 12- and 24-month-old mice, and they found noticeable improvements in various aging-related molecular biomarkers. Interestingly, an increase in median lifespan was also observed. Later, researchers designed an AAV9 vector that expressed Tert in heart tissue to treat heart failure after myocardial infarction (MI). Intravenous injection of this vector into mouse models of myocardial infarction showed that mice with the vector expressing TERT had less damage to the cardiac indices of both structure and function, decreased mortality and improved biomarkers.
KL, another classic aging-related gene, has a much shorter research history than that of the TERT gene, just over twenty years. Exploring concrete mammalian models (mostly mouse models) of aging-related diseases has revealed the therapeutic effect of enhancing KL expression in neurodegenerative diseases, chronic kidney diseases, cardiovascular diseases, etc. Preclinical evidence has demonstrated that KL has broad therapeutic promise for treating various aging-related diseases. However, no interventional clinical trials have been conducted to assess the clinical potential of KL.
The entire human body is widely affected by vascular endothelial growth factor (VEGF), and the formation and function of blood vessels are highly reliant on VEGF. VEGF is negatively associated with aging, and its high VEGF expression has a protective effect on the cardiovascular system. However, many studies have identified it as a potential target in malignant tumors and it is regarded as a promoting factor. Therefore, it remains a concern whether it will induce cancer when applied in anti-aging gene therapy. Researchers conducted an experiment based on the hypothesis that vascular aging is a founding factor in organismal aging. Over an experimental period of more than 30 months, they reported increased lifespans and physiological function after applying the gain-of-function system of transgenic VEGF and AAV-assisted VEGF transduction. Thus, VEGF seems to play a paradoxical role in aging similar to the telomerase gene, which inspires further systematic and careful exploration of potential treatments.
Gene therapies, especially in the field of aging provide new hopes for treating diseases. However, not all aging-related genes have the potential to be the targets. Satisfactory efficacy is only achieved by combining them with an adaptive operational strategy and efficient carriers. Additionally, some genes may simply be predictors of prognosis or capable of screening out effective medications for diseases. To be a therapeutic target, the candidate gene should have a relatively distinct and clear role.
David Sinclair – Slowing down Aging
How Gene Therapy is Changing the Future of Medicine
Peter Diamandis – Human Longevity and The Future
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