If you have an interest in telomerase research, and anyone following developments in the science of aging really should pay attention to telomerase research, then you might find a recent special issue of Genes to be worth reading. It collects a dozen or so papers on the subject, adding to a growing number of reviews, calls to action, and discoveries published in the last couple of years in the field of telomere and telomerase biology. You might look at a very readable review from Maria Blasco's lab, published earlier this year, for example. The researchers there are leaders in telomerase gene therapy, and have demonstrated benefits and a slowing of aging in mice via this path. It remains to be seen how well it will translate to humans, though there are certainly people out there willing to try.
It is possible to describe cancer and aging as two sides of the same coin; the evolved systems that act to suppress cancer also suppress tissue maintenance, and the decline in stem cell activity with age that causes a slow decay of tissue function is a trade-off, balancing death by cancer against death by frailty and organ failure. Cellular replication and growth is the commonality in cancer and maintenance: one is uncontrolled growth, the other controlled growth. One of the most important mechanisms in our cellular biochemistry is the Hayflick limit, and telomeres are a part of the system that creates that limit. Telomeres are lengths of repeated DNA that cap the ends of chromosomes. Every time a cell divides some of that length is lost. When telomeres become too short, a cell halts replication and either destroys itself or becomes senescent and is soon thereafter destroyed by the immune system. Healthy tissues are in a state of balance between loss of cells to the Hayflick limit and the delivery of new cells with long telomeres, created by stem cells. How do stem cells constantly create new daughter cells with long telomeres? They use telomerase to maintain long telomeres: the primary function of telomerase is to add more of the repeating telomeric DNA sequences to the ends of chromosomes.
This ornate situation has evolved because it ensures that cancer incidence is kept low enough for it not to impede evolutionary success. The majority of cells have a limited ability to replicate, and only a small number of cells have unlimited replication rights. This greatly reduces vulnerability to cancerous mutations. Still, cancer happens, and it occurs when cells mutate in one of the few ways that can unlock telomerase or alternative lengthening of telomeres activity, or when stem cells mutate in ways that break their regulatory programs. For cancer researchers, interfering in telomere lengthening is the road to the grail of a universal cancer therapy, a single way to shut down all of the hundreds of types of cancerous tissue. On the other side of the coin, for aging, increased telomerase activity is thought to be a way to spur greater tissue maintenance in older individuals, though the processes by which this happens are many, varied, and much debated, just as the full list of mechanisms of action for stem cell therapies is a matter still under investigation. There is some thought that an increased level of telomerase activity will increase cancer risk, as damaged cells will be allowed to replicate far more often than they have evolved to replicate. Though by the same token, stem cell therapies should be similarly risky. So far the benefits look to outweigh the harms. It may be that our evolutionary point of balance has a fair amount of wiggle room.
The activity of the reverse transcriptase telomerase is a canonical function to maintain telomeres, the ends of linear chromosomes. Telomeres shorten in the absence of telomerase, causing senescence and ageing. In contrast to other organisms, telomerase activity is downregulated early in development in many somatic human tissues. However, some cell types, such as lymphocytes, adult stem cells, and endothelial cells retain, or can upregulate, telomerase activity. Importantly, this activity is strongly controlled by physiological conditions. In contrast, telomerase activity is continuously expressed at a high level in the majority of cancer cells, contributing to their indefinite proliferation potential. Although telomerase activity has been vigorously investigated over the last few decades, many questions still remain open regarding the mechanisms of physiological regulation in normal cells, as well as its up-regulation during tumourigenesis. The complex regulation at the levels of transcription, splicing, and posttranscriptional activation certainly contribute to that. Recently, interventions into its activation to counteract telomere shortening in healthy tissues, as well as its inhibition as tumour therapy, have been suggested and trials have been started with no final breakthrough yet. Thus, we still need to better understand the biology and regulation of telomerase activity in order to interfere with it successfully.
The vast body of literature regarding human telomere maintenance is a true testament to the importance of understanding telomere regulation in both normal and diseased states. In this review, our goal was simple: tell the telomerase story from the biogenesis of its parts to its maturity as a complex and function at its site of action, emphasizing new developments and how they contribute to the foundational knowledge of telomerase and telomere biology. Telomeric integrity has implications in both cancer and aging, as telomere attrition serves as a key checkpoint in the control of cell proliferation by triggering replicative senescence. There are two broadly defined mechanisms of telomere maintenance in humans: telomerase-mediated maintenance and ALT (alternative lengthening of telomeres). However, the complexity of each of these mechanisms becomes more evident with every new publication in the field of telomere biology. Approximately 80% of cancers are immortalized by constitutive activation of telomerase to maintain telomeres throughout rapid cellular proliferation. Additionally, defects in telomerase and other telomere maintenance components cause premature aging syndromes like dyskeratosis congenita (DC), due to progressive telomere shortening and subsequent proliferative blocks. As such, greater knowledge of telomerase regulation and its contribution to telomere homeostasis will contribute to our understanding of human disease and natural cellular processes alike.
Many chronic conditions in humans are associated with chronic inflammation, immune system impairment and accelerated aging. In addition, abnormalities in telomere/telomerase system of these patients have been reported in many of these disorders. Since telomerase, an enzyme directly associated with aging, is inactive in most cell types in a mature organism and active in immune system cells, one can easily hypothesize that the immune system dysfunction/accelerated aging observed in chronic conditions is connected with telomeres and telomerase biology. Indeed, a connection of this nature seems to exist since shortened telomeres, observed in aged cells, cause an inflammatory cascade whereas, at the same time, NF-κB, a master regulator of inflammation, seems to directly induce telomerase transcription as stated above. Moreover, many researchers documented correlations between lower telomerase activity and/or shorter telomeres in immune system cells and elevated cytokines in blood serum from patients with chronic disorders. One should also bear in mind that, although aging is a multifactorial and complex procedure, healthy aging and longevity are believed to be associated with longer telomeres and lower inflammation profiles among older individuals. Despite all of the above, and despite the accumulating data of a strong interconnection between telomerase regulation/activity and inflammation, the mechanistical details and the molecular pathways of this connection have not been uncovered yet.
Emerging evidence over the last decade supports the idea that telomere length-independent functions of telomerase are also important for its function, both in normal and tumor cells. Interestingly, current research also revealed that telomeres may sense cellular stress (such as genotoxic stress, oncogenic or aneuploidy-inducing mutations) that result from harmful mutations that lead to genome instability and induce senescence in cells with intact checkpoints. Although the mechanistic details of the 'sensing' process are yet to be revealed, this new function of telomeres, thought to be a result of accumulating replication stress at the telomeres, seems to be independent of telomere length. In this context, telomerase relieves this cellular protective mechanism by mitigating telomere replication stress and this function of telomerase apparently is separate from its telomere elongation activity. In light of the recent discoveries hinting at novel, telomere length-independent roles of telomeres and telomerase, attempts at modulating telomerase activity to improve organ function and longevity must be seriously reconsidered. In this line, interfering with telomerase activity and its extracurricular functions for cancer therapy seems to be an attractive strategy again but new concepts need to be taken into account.
Aging is one major risk factor for the incidence of cardiovascular diseases and the development of atherosclerosis. One important enzyme known to be involved in aging processes is telomerase reverse transcriptase (TERT). It has been proposed for a long time that telomerase activity is absent from human somatic cells. However, there is accumulating evidence that substantial telomerase activity is present in differentiated, non-dividing somatic cells of the cardiovascular system. This is of particular importance since cardiovascular diseases (CVD) are still the leading cause of death worldwide. All of these diseases have a primary defect in the heart or in the blood vessels, and there is emerging evidence that telomerase has a protective effect against CVD. Understanding this enzymes' functions in these tissues could, in the long run, help to reveal the therapeutic potential of activating TERT in cardiovascular diseases.