Top Journal Reveals Keys to Telomere Length and Human Disease (Part 3 of 3)

Summary: This is part 3 of an extensive new study on the recent discoveries of the role of telomere length in human diseases and aging.  Part 1 on the reliability of telomere length is here. Part 2 on the role of telomere length in cancer is here. [This article first appeared on the website LongevityFacts.com. Author: Brady Hartman. ]

In a comprehensive study published a little more than a week ago in a highly respected journal of the Royal Society of the UK, authors Abraham Aviv and Jerry W. Shay (see bios here) report on the role of telomere length in cancer and degenerative conditions such as respiratory diseases and dementia.

Researchers don’t know if telomere shortening is a symptom of accelerated aging or a cause of it. Researchers have found that psychological stress accelerates telomere shortening and epidemiologic studies link telomere shortening with chronologic aging.

Some researchers consider telomere integrity as a subset of macromolecular damage because there is evidence supporting the notion that telomere shortening leads to harmful effects by activating the DNA repair response and inducing cellular senescence.

What Are Telomeres?

Looking like the plastic tips on the ends of shoelaces, telomeres are the protective caps on the ends of all human chromosomes. Physicians know that abnormally short telomeres due to genetic mutations accelerate the diseases of old age and scientists suspect that telomeres cause the aging process itself.

Is Longer Better When It Comes to Telomeres?

Telomeres grow shorter as we get older. The widespread view regards the pace of this shortening as a ticking biological clock, and people with short telomeres are considered biologically older than their peers because their telomere clock is ticking at a faster pace. Based on the premise that aging and short telomeres are harmful, numerous researchers link short telomeres with detrimental traits and potentially harmful environmental factors. Short telomeres have become synonymous with poor health, both mental and physical, regardless of a person’s age. Such a view is short-sighted, say authors Aviv and Shay, since both short and long telomeres exact a price.

Does Telomere Length Cause The Diseases of Aging?

To test out the role of telomeres, researchers conducted experiments using mice that are genetically engineered to be deficient in telomerase and other telomere-maintenance proteins. These experiments confirmed that short telomeres lessen the lifespan of mice, but only after several generations. This effect is due to that fact that inbred strains of mice have very long telomeres. In fact, it requires a sustained deficiency in telomere maintenance for several generations to shorten telomere length to impact the health and longevity of these mice.

Some people are afflicted with rare human diseases – such as idiopathic pulmonary fibrosis and dyskeratosis congenita – caused by inherited genetic mutations. These genetically inherited illnesses are marked by critically short telomere length and result from mutations in the proteins that regulate telomere length. Researchers genetically engineered mice to model these rare human diseases that stem from single mutations.

While these mice successfully modeled the rare human diseases, the same can’t be said when it comes to modeling the role of telomeres in chronic diseases of aging, principally cancer, and cardiovascular disease. Genetically engineered mice are less successful models of these chronic diseases which are complex human traits driven by multiple genes and gene-environment interactions. Telomere biology plays a subtle role in these human traits with numerous genes. Moreover, telomere biology cannot explain the susceptibility or resistance to a particular disease. As well, the epidemiological studies of telomere length are shaky evidence on which to base conclusions about the role of telomeres in chronic diseases. As A+S put it,

“For these reasons, our present understanding of the connection in the general population between TL [telomere length] and these adult-onset diseases has been derived mainly from epidemiology and population genetics, disciplines that generate associative data, which are usually insufficient to establish cause-and-effect relationships.”

Two Views of Telomere Length

Telomeres as Biological Clocks

The conventional view is that telomeres are clocks because telomeres become progressively shorter each time a cell divides, and it leads to cellular senescence and eventually to cell death. Based on this premise, believers in the telomere biological clock theory propose that an adult with comparatively short telomeres is biologically older than his peers. This view is bolstered, say the authors, by the observation that the “inter-individual variation in age-dependent LTL shortening [leukocyte telomere length] is largely driven by oxidative stress and inflammation,” who also add that

“Studies in cultured cells found that the G triplets of the telomere repeats (TTAGGG) are highly sensitive to the hydroxyl radical.” Adding “Such sensitivity of telomeres to the hydroxyl radical might augment telomere shortening per stem cell/progenitor cell replication, while the inflammatory response might increase replications of haematopoietic stem cells and progenitor cells.” Continuing with “Together, oxidative stress and inflammation, the hallmarks of adult-onset cardiovascular disease, would therefore augment LTL shortening. “

Believers in the telomere biological clock theory point to the quicker pace of age-dependent telomere length shortening to explain the link observed between short telomeres and many human diseases, such as cardiovascular diseases and psychiatric disorders. The authors add

“These putative mechanisms have provided the context for the inference that associations of short LTL with cardiovascular disease and early mortality in adults are the outcome of a faster age-dependent LTL attrition, principally due to higher burdens of oxidative stress and inflammation. A faster pace of age-dependent LTL shortening has also been invoked in explaining associations of short LTL with a host of human diseases, including psychiatric disorders.”

However, say A+S, given the wide variation in telomere length among newborns – the effects of oxidative stress and inflammation explain only a small fraction of the variation in telomere length observed after birth. The concept that telomere length is a clock whose pace is modified by oxidative stress and inflammation overlooks the fact that the telomere clock is not uniformly calibrated at time zero among all newborns. It also ignores the role of telomere length at birth as a principal determinant of telomere length throughout life.

This leads to the conclusion that without the ability to scale an individual’s telomere length to his telomere length at birth, telomere length is a poor proxy for measuring biological age. Moreover, the authors add that while longitudinal studies show that adults with a higher atherosclerotic burden and insulin resistance have shorter telomeres, there is no evidence of a higher rate of age-dependent telomere shortening in these individuals when compared to their peers.

Telomere Length and Chronic Diseases

Another camp believes in the alternative view of telomere length – the belief that telomere length determines the pace of the chronic diseases of adults. The wide telomere length variation among newborns and children suggests a considerable influence of telomere length in early life on telomere length throughout the rest of the life. This fact does not challenge the role of oxidative stress and inflammation in the link between short telomeres and cardiovascular disease. However, the variation in an individual’s inborn telomere length suggests that the role of oxidative stress is small compared to telomere length at birth and during childhood, a phenomenon called telomere length precedence.

Telomere Length Precedence

Telomere length is primarily determined before adulthood, decades before the onset of chronic diseases. Most people who enter adulthood with short telomeres maintain short telomeres throughout their life. As well, most individuals who enter their adult years with long telomeres keep these long telomeres throughout their life. Also, the view that inflammation and oxidative stress explain the association of short telomeres with a cardiovascular disease does not explain the fact that longer telomeres are associated with some cancers.

Telomere Length Directionality

New evidence shows that evolutionary forces face a trade-off between longer telomeres and shorter ones in the chronic diseases of aging. Short telomeres predict increased cardiovascular disease risk, while long telomeres predict increased cancer risk. Short telomeres increase the risk of tissue degeneration and the diseases that accompany it, such as cardiovascular disease. On the other hand, longer telomeres increase the risk of primary cancers.

Genetic Risk Scores and Telomere Length

Genetic analyses provide additional support for the alternative view of telomere length, and telomere length-based genetic risk scores predict disease risk. Researchers performed genome-wide association studies (GWAS) and mapped telomere length-associated single-nucleotide polymorphisms to locations on the human chromosomes, the majority of which harbor the genes which maintain telomere length. Researchers then developed genetic risk scores based on these single-nucleotide polymorphisms to predict susceptibility to cancer and cardiovascular disease.

When the genetic risk score predicts short telomeres, it increases the probability of developing cardiovascular disease, and when the genetic risk score predicts long telomeres, it increases the likelihood of developing cancer.

Role of Telomere Length in Chronic Disease

Aviv and Shay sum up evidence supporting the view that telomere length determines the pace of the chronic diseases of adults. A+S say the individual findings of telomere length precedence, telomere length directionality, and genetic risk scores do not prove causality. However, when taken together, they provide compelling support for the idea that telomere length influences cancer and cardiovascular disease —the two conditions that largely determine longevity in the US and most of the world.

Based on this conclusion A+S suggest that mechanisms other than oxidative stress and inflammation during adulthood explain the variation in telomere length among individuals and the association between telomere length and disease. These include the diminished ability for replication and repair when telomeres are short and increased risk of tumors when telomeres are long. This idea is particularly relevant to tumors, given that telomere biology is at the crossroads of the interaction between cancerous mutations and cell replication dynamics. Moreover, say A+S, the idea that telomere length contributes to cancer and cardiovascular disease

“aligns with the general notion that evolutionary forces fashion LTL [leukocyte telomere length] in mammals through balancing two diametrically opposing forces: cancer and degenerative diseases.”

Telomere Length, Cancer and Cardiovascular Disease

The authors point out that the risk of cardiovascular disease or cancer due to short or long telomeres is small. However, this might be because the optimal telomere length strikes a balance between these two diseases, as A+S say

“It is noteworthy that the overall risks of cardiovascular disease or cancer due to respectively short or long telomeres may be small. However, this might be because the optimal TL [telomere length] strikes a balance between these two disease categories and shifts their impact primarily to the post-reproductive years. All else being equal, an upward or downward drift in the average TL by 1–2 kb would probably result in a respective upsurge in cancer or cardiovascular disease incidence in the general population. For this reason alone, it is of interest to understand the factors that maintain the optimal human TL across generations, the dynamics of which is probably tailored to the genetic makeup in particular environmental settings.”

Bottom Line on Telomere Length

One camp likens telomeres to a ticking clock. The other camp believes that long telomeres are healthy while short telomeres are not. Aviv and Shay say that these two schools of belief must be tempered by understanding that

“in the general population telomeres ostensibly converge to an optimal length, which probably strikes a balance between the advantages and disadvantages of having relatively short versus long telomeres.”

Series Articles on Telomere Length

Part 1 on the accuracy of telomere length is here. Part 2 on the role of telomere length in cancer is here.

This article is featured in the best of telomere reports series.

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References

Cover photo credit: Dr_Microbe / iStock / Getty Images.

Abraham Aviv, Jerry W. Shay. “Reflections on telomere dynamics and ageing-related diseases in humans.” Philosophical Transactions of The Royal Society B Biological Sciences, Published 15 January 2018.DOI: 10.1098/rstb.2016.0436. Link to Article.

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Tags: Cancer, Lengthen Telomeres, Telomeres