Telomere Dynamics:

From Clinical Implications to Lifestyle Factors

AROHI MUKHOPADHYAY
ABSTRACT:
The world's geriatric population is having a big impact socially and
economically, making geriatric research really important. Scientists are focusing
on the hallmarks of aging, which are the different ways our bodies change as
we get older. One key area they're studying is telomere biology. Telomeres are
cap like structures present in the end of chromosomal arms. These telomeres
are held directly responsible for ageing, age related diseases and dangerous
diseases including Alzheimer’s and Cancer. This article is a review on the effects
of the lengths of these telomeres and factors that affect their lengths

INTRODUCTION:
In the past hundred years, progress in public health and medicine has led to a
significant increase in global life expectancy. On the current trajectory, 2.1
billion individuals will be older than age 60 by 2050 (United Nations, 2017).
This demographic shift will bring about significant rises in age-related illnesses
such as Alzheimer’s disease, cardiovascular disease, and cancer (The genetics
of human ageing). These conditions are expected to double in frequency
approximately every five years after individuals reach 60 years of age. Without
advancements in medical and wellness approaches, the global community will
face an unsustainable burden of chronic illnesses, already imposing substantial
social and economic costs. The link between aging and such diseases has
motivated fundamental investigations into the mechanisms of aging and
strategies to reverse its effect.
Aging is a progressive degenerative state accompanied by tissue stem cell
depletion, tissue inflammation, matrix alterations, cellular aging, and metabolic
dysfunction. These cellular and tissue changes reflect in changes in molecular
level in the mitochondria, intercellular communication, nutrient sensing and
DNA repair that leads to genomic instability . (The Hallmarks of Aging)
Telomeres are the repetitive nucleotide sequences (A nucleotide is an organic
molecule with a basic composition of a nitrogenous base, pentose sugar and
phosphate) that are present on the chromosomal endings in form of a cap like
structure. It is present in eukaryotic chromosomes. These are non-coding
regions and do not code for any protein.
In most of the prokaryotes, DNA is circular so telomeres are not found. In some
of the prokaryotes with linear DNA, telomeres are found but the structure is
different from those of eukaryotic cells. They are in the form of a hairpin loop
formed by a single strand or bound to proteins.

A further dive in in the details of genomic instability have led us to find the root
cause of telomere dysfunction.
This review offers a comprehensive look at the evolution and present status of
telomere research. It explores the systematic connections between telomere
malfunction and aging indicators, and delves into the widespread influence of
telomeres and telomerase in influencing characteristics of aging, prevalent age-
related illnesses like neurodegeneration and cancer. The review also discusses
how the close association between telomeres and aging mechanisms guides
the advancement of strategies aimed at combating aging and preventing
diseases and contradictions of them.

TELOMERES AND THEIR FUNCTIONS

Telomeres are protective structures located at the ends of eukaryotic
chromosomes. Composed of repetitive DNA sequences and associated
proteins, their primary role is to safeguard the genetic material from
degradation and prevent chromosomes from fusing with neighboring DNA
strands.
Telomeres also play a crucial role in cellular processes by ensuring the integrity
of chromosomes during DNA replication and cell division. They help maintain
chromosomal stability and prevent DNA damage responses that could
otherwise lead to genomic instability and cell malfunction .

HISTORY OF TELOMERES AND TELOMERASE:

The concept of telomeres was born in the 1930's when McClintock (A
Correlation of Cytological and Genetical Crossing-Over in Zea Mays) and
Muller inferred the existence of a unique structure at the ends of
chromosomes. Muller coined the term “telomere” from the Greek word telos,
meaning “end,” and meros, meaning “part”; hence, “end part”
In 1961, it was shown that human fetal cells had a limited ability to replicate,
typically undergoing 50 to 60 doublings. This phenomenon was later named
the "Hayflick limit" or replicative senescence.(The serial cultivation of human
diploid cell strains)
In the early 1970s, Olovnikov (1973) and Watson (1972) introduced the
concept of the "end replication problem." They observed the asymmetry in
linear DNA replication and predicted that during each cell division,
chromosomal DNA would experience loss from the ends of the lagging strand
due to the removal of the terminal RNA primer. This process results in
progressive chromosomal shortening over time.

TELOMERASE AND TELOMERASE NEGATIVE CELLS

Telomerase-negative cells are cells that lack or have very low levels of
telomerase activity. Telomerase is an enzyme responsible for adding repetitive
DNA sequences to the ends of chromosomes, known as telomeres, thereby
counteracting their natural shortening during DNA replication.
In organisms such as humans, most somatic cells (cells other than germ cells)
are telomerase-negative. This means that with each cell division, their
telomeres progressively shorten due to the end replication problem, where the
RNA primer is removed from the lagging strand during DNA replication.
Eventually, when telomeres become critically short, these cells enter a state of
replicative senescence or undergo apoptosis (programmed cell death).
Telomerase-negative cells include many types of differentiated cells in the
body, which have limited replicative potential due to telomere shortening. In
contrast, stem cells, germ cells, and certain immune cells maintain telomerase
activity to varying degrees, allowing them to maintain telomere length and
proliferative capacity over multiple divisions.

EFFECTS OF TELOMERE SHORTENING

Telomere shortening significantly impacts us by influencing cellular aging and
contributing to age-related diseases. Telomeres, protective caps at the ends of
chromosomes, naturally shorten with each cell division due to the end
replication problem. As telomeres reach a critical length, cells may enter a state
of senescence or undergo programmed cell death (apoptosis), limiting their
ability to replicate and function effectively. This process is considered a marker
of biological aging, as individuals with shorter telomeres tend to experience
age-related health declines earlier.
Telomere shortening also plays a role in disease susceptibility. Shortened
telomeres are associated with an increased risk of various age-related
conditions such as cardiovascular disease, diabetes, neurodegenerative
disorders, and certain cancers. This correlation is partly due to the impaired
regenerative capacity of tissues and the accumulation of dysfunctional cells
over time.
Furthermore, telomere dysfunction can lead to genomic instability, where
chromosomes become prone to structural abnormalities and mutations. This
instability contributes to disease development and progression, impacting
overall health and lifespan.
IN ATTEMPTS OF PREVENTING AGEING
Thus from the previous study we might realise to prevent ageing and age
related diseases we will have to attempt to elongate the telomere length or
adjust telomerase levels. However telomere elongation comes with its own
hurdles too.

TELOMERES AND CANCER

Telomere elongation through activation of telomerase enzyme is a feature
commonly observed in cancer cells. Cancer cells typically activate telomerase
to maintain their telomere length, allowing them to divide continuously
without undergoing senescence or apoptosis (programmed cell death) due to
telomere shortening.
Telomere attrition acts as a natural barrier against the formation of tumors,
functioning as a tumor suppressor pathway. When cells experience telomere
shortening due to repeated divisions, they typically respond by stopping their
growth or undergoing programmed cell death, which helps prevent cancer.
However cells lacking the key elements to response of cell senescence and
apoptosis they may fail to respond to signals from ATR and ATM proteins at
shortened telomeres. This failure allows cells to continue dividing despite
telomere shortening, leading to a state called telomere crisis.
To escape telomere crisis and sustain unchecked growth, cancer cells often
activate telomerase, an enzyme that elongates telomeres. This telomerase
activation allows cancer cells to stabilize their chromosomes and evade the
consequences of telomere shortening, facilitating the progression and
proliferation of tumors with a highly rearranged genome.
Telomeres in cancer: tumour suppression and genome instability

MAINTENANCE OF TELOMERE LENGTH WITHOUT SYNTHETIC

MANIPULATION OF TELOMERASE
Studies have shown maintenance of telomere length is the most safest
methods to prevent unnecessary risks of diseases and a healthy life. Unwanted
shortening and elongation can be prevented by maintaining a health lifestyle :
(1) Eating Nutritional food:
A balanced diet rich in antioxidants, vitamins (such as vitamin D and B
vitamins), and minerals (like zinc and magnesium) supports telomere
maintenance and function. Conversely, diets high in processed foods,
sugars, and unhealthy fats may promote oxidative stress and inflammation,
accelerating telomere shortening.
(Oxidative stress shortens telomeres)
However we must keep in mind nutrients in its natural form is the best way
of intake and their synthesis. Recent researches have shown that long-term
multi-supplement users had longer telomere length in their 50s, 60s and
70s compared to controls. The results suggest that heavy dietary
supplementation may lead telomere shortening accompanied with
improved health and nutritional status. Supplement users intaking
supplements containing vitamins C, D and E, carotenoids, omega-3 fatty
acids and polyphenols may all contribute to the effects on telomere length.
(Telomere_Length_of_Multiple_Dietary.pdf (chiro.org)
The role of telomeres and vitamin D in cellular aging and age-related
diseases
(2) Physical Activity:
Regular exercise has been associated with longer telomeres due to its ability
to reduce oxidative stress and inflammation. Both aerobic exercise and
resistance training have shown beneficial effects on telomere length and
overall cellular health

(3) Stress Management

Chronic psychological stress can accelerate telomere shortening through
increased oxidative stress and inflammation. Practices like mindfulness
meditation, yoga, and relaxation techniques may help mitigate stress and
support telomere maintenance.
(Can Meditation Slow Rate of Cellular Aging?)
(4) Sleep:
Poor sleep quality and insufficient sleep have been linked to shorter
telomeres. Adequate and restorative sleep is essential for cellular repair
processes, including telomere maintenance.
(5) Smoking and Alcohol Consumption:
Smoking and excessive alcohol consumption contribute to oxidative
stress and inflammation, which can accelerate telomere shortening and
increase the risk of chronic diseases associated with aging.
(6) Environmental Factors:
Exposure to environmental pollutants, toxins, and ultraviolet (UV)
radiation can induce oxidative stress and DNA damage, affecting
telomere integrity and accelerating cellular aging.
(7) Social Connections:
Strong social relationships and support networks have been linked to
longer telomeres. Social isolation and loneliness, on the other hand, may
contribute to stress and poor health outcomes that can impact telomere
length.
(8) Obesity and Metabolic Health:
Obesity and metabolic conditions such as insulin resistance and diabetes
are associated with shorter telomeres. Maintaining a healthy weight and
managing metabolic health through diet and exercise can support
telomere maintenance.

CONCLUSION:
In conclusion, the study of telomeres reveals their crucial role in
cellular aging and overall health, influenced significantly by both
intrinsic factors such as genetics and extrinsic factors like lifestyle
choices. Understanding the impact of telomere length on longevity
underscores the importance of adopting healthy habits such as regular
exercise, balanced nutrition, stress management, and adequate sleep.
These lifestyle practices have been shown to potentially mitigate
telomere shortening, offering promising avenues for promoting cellular
health and overall well-being across the lifespan. Further research into
targeted interventions and personalized approaches are continued by
researchers to advance the understanding of telomeres and their
implications for healthspan and longevity.