Telomeres and diseases (4)
Telomeres and aging
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Telomeres shorten as we age. Accordingly, telomere length was recognized as an indicator of "genetic age" (mitotic clock) and a fundamental explanation of the aging process, and was positioned as a simple prognostic factor of longevity. Telomere length measurement kits have been offered in combination with recommendations for lifestyle changes and drug therapy, although neither is based on the results of properly conducted clinical studies. Simple but attractive arguments concerning the relationship between telomere length and aging should today be viewed with a certain degree of skepticism as contradictory, simplistic and potentially dangerous. Telomere length really reflects the proliferative history of the cell and its predisposition to apoptosis, physiological aging and transformation in the future. However, cellular aging is not the equivalent of aging at the organ and organizational levels.
There are several ways to justify the relationship between telomere biology and aging. Firstly, there is a physiological overlap between the length of the shortest telomeres of young children and the longest telomeres of elderly people. The most significant shortening of telomeres occurs in the early stages of life against the background of active growth and, in general, low morbidity. The classic telomere syndrome in congenital dyskeratosis is not at all typical for progeria, a group of hereditary syndromes in which premature aging of patients is characterized not only by typical external signs, but also by the development of age–related diseases such as atherosclerosis and dementia. On the contrary, the organ damage observed in congenital dyskeratosis is not similar to the changes occurring during physiological aging of the bone marrow, lungs and liver. The number of bone marrow cells of elderly people decreases slightly, but the number of stem cells may increase, and the concentration of blood cells remains stable. Under normal conditions, fibrosis is not observed in the liver or lungs of aging people. Despite the fact that an association was found between relatively short leukocyte telomeres and the risk of developing cardiovascular diseases in adults, clinical correlations were not unambiguous and may be associated with general exposure to reactive oxygen species.
There have also been attempts to clarify the relationship between short telomeres and longevity in human studies. In a provocative preliminary paper published by scientists at the University of Utah, it was found that people aged about 60 years with the longest telomeres lived longer than people of the same age with the shortest telomeres. However, the most common cause of death in the latter group was, oddly enough, infections, while shorter telomeres did not increase the frequency of deaths due to cancer [19]. Mortality due to heart disease was also higher among participants with the shortest telomeres.
Subsequent work has brought contradictory results. The Cardiovascular Health Study program with the participation of people over the age of 65 showed that the risk of death of patients corresponding to the quartile along the shortest telomere length was 60% higher than for patients corresponding to the quartile along the longest length [20]. Infections were again the cause of mortality associated with the shortest telomeres. Two studies involving elderly twins also revealed a correlation between short telomeres and poor survival [21,22]. And finally, an Italian cohort study in which participants were followed for 10 years also showed that mortality over 10 years is significantly higher among people with the shortest telomeres [23].
At the same time, these associations were not confirmed in other studies involving elderly people. Blackburn and Cauthon published data according to which telomere length was not a prognostic factor in assessing life expectancy, but correlated with the duration of a healthy life period [24].
In a Danish study involving people aged 73 to 101, the authors demonstrated that telomere length correlated with life expectancy when using a simple one-factor analysis, but when adjusted for age, it did not allow to predict longevity [25]. In a cohort of Dutch men with an average age of 78 years, telomere length decreased with aging, but did not correlate with mortality [26]. In a Finnish study, telomere length did not predict overall mortality [27]. Finally, an analysis conducted in California showed that the short length of telomeres predicted mortality from diseases of the cardiovascular system in women, but not in men, then the prognostic factor of mortality was the rate of telomere shortening, and not their actual length [28].
There may be several reasons for these discrepancies. In some analyses, telomere length indicators could be considered as surrogate markers of age. In addition, retrospective studies may reveal "positive" associations that are random and not reproduced during subsequent studies.
In a mouse model of telomerase deficiency and accelerated telomere shortening, researchers found that low telomerase expression disrupted the functioning of certain intracellular mechanisms involved in mitochondrial functioning and glucose metabolism, which ultimately led to heart muscle disease [29]. Interestingly, telomerase reactivation in such animals restored glucose synthesis and heart function. However, the abnormalities observed in mice with telomerase deficiency are not similar to the abnormalities typical for people with very short telomeres who rarely suffer from heart disease.
Extrapolation of the results obtained from the study of telomeres in mouse models to human physiology and diseases should be approached with caution. Mice are not an ideal model of telomere shortening and its effect on aging: their telomeres are 5-10 times longer than human ones, despite an incomparably shorter lifespan. Mice with "knocked out" telomerase lead a normal healthy life for several generations. Even though animals of the last generation with very short telomeres are infertile, they do not demonstrate clinical phenotypes characteristic of human telomeropathies (bone marrow insufficiency, lung fibrosis, liver cirrhosis). In addition, unlike people with defective telomerase, who are at high risk of developing cancer, mice with a similar defect are not characterized by an increased incidence of cancer, except for variants with simultaneous suppression of p53 gene activity.
Ending: Telomeres in regenerative medicinePortal "Eternal youth" http://vechnayamolodost.ru