There is a growing interest in the delivery of additional telomerase to tissues, usually via gene therapy, as a method to either partly reverse the progression of some specific symptoms of aging, or to slow the progression of aging in general. The open access research linked below is an example of the type, with the authors focused on measures relating to cellular senescence and atherosclerosis in the vascular system.
Delivery of telomerase to tissues is one of many potential approaches to generating increased stem cell activity. Everything from stem cell transplants through to exercise may produce at least some of its effects by either slowing or temporarily reversing the characteristic decline in a patient's stem cell activity with age. Stem cells are responsible for maintaining tissues, delivering a supply of new cells to replace those come to the end of their useful life spans. The loss of stem cell activity over the course of a lifetime, most likely regulated by epigenetic changes that are themselves a reaction to rising levels of cell and tissue damage, is thought to be an evolved balance between death by cancer (too much stem cell activity in age-damaged tissues) and death by organ failure (too little stem cell activity in age-damaged tissues). One of the most interesting developments in the growing scientific industry of stem cell manipulation is that treatments, experimental and clinical, have so far produced less cancer than feared at the outset. There may be a fair amount of wiggle room in the evolved balance to make things better via increased stem cell activity.
Stem cell activity isn't really the goal of the researchers here, however. They want to activate telomerase in all cells in the vascular system, not just stem cells, aiming to reduce the number that become senescent and suppress the harmful activities of those that are senescent. Senescent cells accumulate in tissues with age, and when present in greater numbers they cause significant harm, generating chronic inflammation, degrading tissue structure, and altering the behavior of surrounding cells for the worse as well. The goals of the researchers here are more akin to the goals of early efforts to produce treatments based on telomerase, building on its primary function of lengthening telomeres. Telomeres cap the ends of chromosomes and are a part of a counter mechanism that determines cell life span: each cell division results in the loss of a little telomere length, and when they become too short the cell self-destructs or becomes senescent. In human somatic cells, the vast majority of any tissue, there is no telomerase activity, and the counter only counts down. The stem cells supporting that tissue use telomerase to maintain their cell lines indefinitely, however, retaining the ability to deliver new cells with long telomeres to replace those that have reached the end of their replicative life span. Thus average telomere length in tissue is some function of how fast cells replicate and how fast new cells are delivered. This average seems to decline with aging, but is fairly dynamic on shorter timeframes, given transient illness and other changing circumstances.
This whole baroque system probably evolved due to the constraints imposed by cancer. Limiting unfettered replication to only a tiny proportion of cells must be in some way absolutely necessary to produce large, complex animals. Delivering telomerase to somatic cells obviously puts a large thumb on one side of the balance here, and this is where the concerns about cancer continue to appear pressing enough for caution. Still, we have telomerase gene therapy in mice producing extended healthy life spans and being used to treat heart attacks. It seems certain based on the evidence to date and the breadth of interest that this is going to be tried in human medicine by more than just the adventurous startups at the head of the pack.
For my part, this all looks like work that isn't quite aligned with the goals of damage repair after the SENS model. If it produces benefits over and above the present state of medicine, then great. But if we think that aging is caused by damage, then overriding either stem cell decline or the senescent state still needs to be coupled with repair of cell and tissue damage: mitochondrial DNA, amyloids, lipofusin, cross-links, and so forth. It is arguably the case that dealing with those forms of damage would in and of itself restore stem cell activity and reduce the development of cellular senescence, returning the tissue microenvironment to a more youthful appearance, and in doing so reduce or remove these reactions to damage. That, of course, remains to be tested. But as for senescent cells, it seems more effective to destroy them than to try to modulate their behavior.
Aging of the vascular system is considered a major contributor in the development of atherosclerotic lesions. The structural and functional integrity of the arterial wall progressively declines with aging, as manifested by endothelial and vascular smooth muscle cell dysfunction, reduced regenerative capacity, and a decline in circulating and tissue resident progenitor cells. Cellular aging and associated cellular dysfunction is caused by multiple factors, such as accumulation of DNA damage, misfolded proteins, and telomere attrition. In some cells, telomere length may be restored by activity of the enzyme telomerase reverse transcriptase (TERT) together with its RNA component (TERC). The ability of embryonic or induced pluripotent stem cells to replicate indefinitely is due to the expression by these cells of functional TERT and TERC. Notably, TERT and TERC are reactivated in about 90% of malignancies, accounting for their transformation into essentially immortalized cells. Accordingly, one potential therapeutic approach to treating some malignancies would be to antagonize the activity of telomerase in cancer stem cell. On the other hand, a transient restoration of telomerase activity to somatic cells could have therapeutic effects. Evidence suggests that inducing telomerase activity in somatic cells and thereby restoring telomere length may reverse cell senescence and restore a functional phenotype.
Cellular senescence of endothelial cells, vascular smooth muscle cells, tissue resident cells, and circulating progenitor cells plays an important role in the early stages of a developing vascular lesion that ultimately leads to an atherosclerotic plaque. Aged endothelial cells manifest increased expression of proinflammatory surface markers, a decrease in nitric oxide (NO) production, and a change of structural phenotype that compromises the barrier function of the endothelial monolayer of arterial vessel walls. Additionally, the decrease in circulating endothelial progenitors fails to compensate for micro-injuries of the arterial vessel wall, in turn exposing the subendothelial vessel structures to circulating factors that further promote lesion formation. Preclinical studies suggest that activation of telomerase can delay or even reverse the senescent phenotype of aged vascular cells.
With aging, phenotypic changes occur within endothelial cells as they switch to an activated state, expressing inflammatory surface markers such as VCAM-1 and ICAM-1 and secreting proinflammatory cytokines. The chronic activation of the immune system and leukocyte recruitment to the dysfunctional regions of endothelial cell layers further accelerates the aging process. Aging of the endothelium is accelerated at sites of disturbed flow such as the iliac artery bifurcation, where the telomeres of human endothelial cells are demonstrably shorter and analysis reveals an increased number of senescent endothelial cells. This accelerated aging at vascular bifurcations may be due in part to the hemodynamic activation of an inflammatory phenotype by low and oscillating shear stress at these sites. Thus, a pathologic cycle of inflammation and aging occurs at the very sites (bends, branches, and bifurcations) where the most severe atherosclerotic lesions typically occur.
This pathologic cycle could potentially be reversed by therapeutic extension of telomeres. Previously, we have shown that aged human aortic endothelial cells manifest many attributes of a senescent vasculature, including reduced ability to proliferate and respond normally to shear stress, to generate nitric oxide, and to resist adhesion of leukocytes. When we transfected these endothelial cells using a lentiviral vector to overexpress telomerase, these senescent properties were reversed. Telomerase transfected endothelial cells made more nitric oxide, manifested fewer adhesion molecules, were less adhesive for mononuclear cells, and had greater replicative capacity. Such changes would be expected to reduce the progression of atherosclerosis if vascular regeneration by telomere extension could be achieved in patients.