Telomeres are structures located at the chromosomal end. These are nucleoproteins with DNA sequence, i.e., TTAGGG in 5′ to 3′ direction, repeated multiple times. These nucleoproteins are bound by a six-protein complex called “Shelterin.” These sequences are repeated about three thousand times. The telomeres cover the end of chromosomes, similar to plastic on the tip of a shoelace. It helps to organize the chromosomes within the nucleus and prevent them from sticking. These also facilitate the division of cells.
In humans, the telomere length ranges from 0.5 to 15 kilobase pairs, but in rodents, the telomere length ranges from 10 – 72 kilobase pairs (Oeseburg et al., 2010). The size of telomeres differs intra-species and interspecies, and the length of base pairs in telomeres also varies (Lansdorp et al., 1996).
In normal adult cells, the telomere shortens in each cell division. When the telomere length approaches a critical point, the vital DNA sequence starts losing, entering the replicative senescence phase, and cell death may occur (Victorelli & Passos, 2017). The rate of shortening of telomeres varies in different chromosomes, tissues, and even species (Cherif et al., 2003). However, the actual loss is less significant than the observed loss as in humans, the observed loss of nucleotides is 15 to 200 base pairs, but the expected loss is ten (Monaghan, 2010).
Telomere dynamics predict chronological age, survival, and mortality in the wild population (Bize et al., 2009). Previously, several studies have been performed to know the relationship between telomere length and the longevity of living organisms (Bize et al., 2009) (Steenstrup et al., 2017).
How telomeres are shortened
In each division, the chromosomes are shortened. The nucleotides from the telomeres are lost in each division, and the DNA remains intact. Without telomere, the critical DNA may lose during cell division. With every division, up to 200 bases are lost from telomeres, and telomeres are shortened with each cell division as the cell division is a continuous process of life; that is why the telomeres also get short throughout life with the increasing age. In this way, the telomere prevents DNA repair that may cause unstable chromosomes and cell senescence. It has been declared an efficient mechanism of genome protection (Meyne & Ratliff, 1989).
Two main factors of telomeres shortening.
The main factors for the shortening of telomeres are “end replication problem” and “oxidative stress.”
The end-replication problem
The eukaryotic chromosome is linear and covered at its ends. The DNA at these ends does not copy during replication and thus causes a problem. The leading strand produces continuously while the lagging stand produces in small pieces known as Okazaki fragments beginning with RNA primer. These Okazaki fragments cannot replace the short part at the end. This uncopied chromosome leaves a single strand extending. After multiple divisions, the chromosomes become shorter and shorter (Chow et al., 2012)
Telomeres are the single strand overhung DNA. As you know, this overhanging is because of incomplete end replication. These single overhang strands join to close double-stranded DNA at complementary repeats and form the telomeres caps (Vega et al., 2003). The proteins linked at the end also prevent them from DNA repair mechanism.
The telomere repeats fade after multiple divisions and protect the inner chromosomal genes. The continuous telomere loss causes aging of the cell, and after a particular time cell deteriorates (Bartlett, 2014).
The other reason for telomere shortening is oxidative stress, which occurs due to the synthesis of reactive oxygen species inside cells that disturbs the antioxidant defenses of the cells. This imbalance causes the pathogenesis of several diseases in the human body, such as neurological, cardiovascular, and respiratory diseases (Hegde et al., 2012).
The (ROS) reactive oxygen species level rises due to mitochondrial disability and inflammation. The inflammation occurs due to the accumulation of immune cells following the infection. The ROS significantly increases in chronic inflammatory illnesses, e.g., ulcerative colitis (Lonkar & Dedon, 2011). The oxidative stress is linked with the shorter telomere length (Sanders et al., 2011).
Telomerase replenishes telomere
Telomerase enzyme helps to retain the telomere length in the specific mechanism. It lengthens the telomeres by using the RNA template to synthesize DNA. The enzymes join the RNA molecule at the repeated sequence of telomeres. The enzymes hang to the hanging DNA strand through the cRNA. After sufficient length, the complementary DNA strand forms using DNA polymerase and RNA primer. As a result, double-stranded DNA is produced.
Usually, somatic tissue and stem cells cannot synthesize telomerase; thus, telomere length is not compensated, and telomeres get shorter with aging. It is functional in germ cells and a few adult cells. Furthermore, surprisingly, the telomerase is active in cancer cells and can be targeted to limit cancer cell division (Holt & Shay, 1999).
Factors responsible for telomere shortening
Several factors are involved in disturbing telomere, including lifestyle and environment. These factors ultimately affect the health and longevity of human beings.
As discussed earlier, oxidative stress damages the telomere metabolism and causes telomere shortening. Oxidative stress can be managed by antioxidant-containing food. Vitamins, minerals, omega-3 fatty acids, and polyphenols lower oxidative stress and prevent telomere loss. The reduced calorie intake also minimizes the telomere shortening. The lifestyle alteration enhances the telomere functioning of peripheral body mononuclear cells by up to 30%. The telomerase activity improvement lowers the risk of cardiovascular disease and the C reactive protein, an aging biomarker. In addition to food intake and lifestyle modifications, improved mental health through meditation also improves telomere activity and its length (Vidaček et al.,2017). Thus you can achieve longevity by improving associated factors that affect the telomere metabolism.
Telomere as a biological marker
Telomere shortening can be used as a biological thermometer to determine several life traits such as longevity and aging. Genetics, epigenetics, and other environmental factors affect human characteristics and telomere length (Njajou et al., 2007).
Several studies have been conducted on organisms with different life spans to determine the association of telomere shortening with chronological age (Haussmann et al., 2003).
Researchers are trying to find a tool to analyze the aging rate. Different factors were studied to evaluate aging, such as grip strength, chair lifting, walking speed, and balanced standing. However, these factors could not analyze the aging and deaths due to chronic diseases. That is why they found the telomere an effective and precise tool to monitor biological aging American Federation for Aging Research (2016) declared the requirement for an accurate aging biomarker, and the telomere contains those properties. Its length makes it an efficient tool for determining aging and the association of chronological aging with disease and mortality (Hastings et al., 2017).
Few studies investigating the importance of telomeres in longevity
A study was conducted to find an association between telomere length and mortality in older people aged 60. The telomere shortens with incredible speed, and patients risk developing many diseases and premature death. The results showed that individuals with shorter telomeres are more susceptible to mortality, which is 8.54 times higher than the deaths due to infectious diseases (Cawthon et al., 2003).
Another study was conducted in worms to investigate the relationship between telomere length and the life span. The effect of telomere length was observed in a nematode, and the extended life period was observed in the nematodes with longer telomeres. Moreover, they investigated that there is no link between telomere length and the cycling of germ stem cells (Joeng et al., 2004).
Several aging-related chronic diseases, including cardiovascular disease and cancer, are also associated with telomere length. In chronic disease, the high oxidative stress causes more significant telomere shortening. Epel et al. (2008) reported increased mortality in females due to cardiovascular disease and decreased telomere length. Moreover, telomere shortening in males aged 70 to 79 is also associated with chronic diseases.
The telomere length was significantly less in the individuals with hypertension (Aviv, 1999), diabetes (Jeanclos et al., 1998), overweight (Valdes et al., 2005), insulin resistance (Gardner et al., 2005), atherosclerosis (Samani et al.,2001), vascular dementia (Von Zglinicki et al.,2000), and cardiac issues (Cawthon et al., 2003)
In another study, the longevity of zebra finches was observed by measuring the telomere length at different life spans. The organisms with telomere length at 25d improve the life span, and other organisms with short telomeres in their early life die earlier. This research shows the importance of telomere length in longevity (Heidinger et al., 2012).
All in all, the telomere is an integral part of chromosomes, preserving the chromosomal gene loss during cell division. The telomere length reduces with each cell division, and after a certain point of shortening, the cell goes to senescence. The telomere shortens due to end replication problems and oxidative stress. Some factors can improve the telomere length and the overall health of individuals. These factors include lifestyle modification, an antioxidant diet, and meditation. Moreover, telomere length is a biological marker for chronological age and chronic diseases. Research has proved that longevity can be improved by improving the telomere length.
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