Telomeres explained: role in genomic stability, stem cells, replicative senescence | Elissa Epel
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Telomeres have been likened to aglets – the little plastic caps on the ends of shoestrings that prevent the string from fraying – and it's a good analogy. Telomeres are distinctive structures comprised of short, repetitive sequences of DNA present on the ends of chromosomes. They protect the genome from damage during regular cell division or under conditions of physiological or emotional stress. Over time, however, telomeres shorten. Telomerase, an enzyme that helps rebuild telomeres, is an important determinant of how long a cell can divide. In this clip, Dr. Elissa Epel gives a brief overview of telomeres and telomerase and explains how they impact health and lifespan.
Rhonda: You mentioned telomeres a few times. So for people listening or viewing that aren't quite familiar with telomere biology, maybe you can give a quick just, you know, background on what telomeres are, and why they are involved in the aging process, why they're biomarkers for aging?
Elissa: Sure. So people like to think of them as like the aglets of the tips of shoelaces, these plastic caps to keep shoelaces from fraying. So when you think of our linear chromosomes, they're all capped at the end with this wound up strings of DNA, repeating DNA called telomeres. And they are protecting the genome from damage. So they're very important that way. They are sensing chemical signals of stress in the cell. And so if there becomes a toxic situation, they think the cells in danger, they are going to... well, that cell can shut down to protect the body. But also the telomeres get worn down very quickly when there's a lot of stress. And so stress biology and aging biology are actually really tied up intimately.
Rhonda: They take the hit, so they're trying to protect your DNA from potentially acquiring a mutation that could lead to something like cancer.
Elissa: Yes.
Rhonda: So they sort of take the hit for the cell?
Elissa: Right.
Rhonda: In your experience, how much would you say that telomere length...so, you know, the telomeres get shorter with time and shorter telomeres are supposed to correspond to aging. How much would you say that telomere length regulates the aging process, like actually plays an active role, versus just is a biomarker, something that is just biomarking the aging process?
Elissa: That's a good question. So telomeres are one specific pathway of how a cell ages, and how our tissue ages. And the pathway is this, it's called replicative senescence and it's basically how long can that cell continue to divide, and divide, and replenish into new fresh young cells. So the telomeres, when they get too short, prevent that particular cell, whether it's an immune cell or a neuron in our hippocampus or the lining of our cardiovascular system, we need those cells to replenish throughout the decades. When it to the telomeres gets too short that cell stops dividing. And so it's basically a little window into how long can these cells continue dividing. If the telomeres are long, they have a long potential for replenishing tissue.
Rhonda: So it sounds like the telomeres are much more important in stem cell populations, populations that are really responsible for replenishing a variety of cell types including tissue.
Elissa: Right, absolutely.
Rhonda: You know, would you say that there's a difference between how telomeres shorten or, you know, what the attrition rate of telomeres and stem cells are versus other cell types that are non-stem cells?
Elissa: Yes. So if we could measure stem cells more easily, we would realize that partly what we're measuring in any tissue is the health and longevity in telomere length of the stem cell. So the stem cells lead to progenitor cells. And then there's all the offspring. And so when we look at blood, we're looking at the offspring in the different circulating cells that roughly reflect the health of the stem cell.
Rhonda: And there's a variety of different...so you're talking about the damage that happens with age and how that can accelerate telomere shortening because they sort of take the hit, they're protecting our DNA. There's an enzyme that can rebuild telomeres right?
Elissa: Right.
Rhonda: Talk a little bit about that enzyme, but it's not active in every cell, correct?
Elissa: Right. So the telomerase enzyme is a very interesting enzyme that is intracellular, that it has the ability to actually rebuild telomeres by adding back base pairs. So it's an RNA reverse transcriptase. And this was discovered by Liz Blackburn and Carol Greider and colleagues, you know, over 25 years ago. And they were showing how if you knock it down, the cells cannot divide anymore. And if you upregulate it, the cells become immortal. So it is an important regulator of how long a cell can divide. It's one of the major determinants of telomere length because if your telomere is shortening and you have a lot of telomerase, you can repair them, you may be even can lengthen them.
Rhonda: And telomerase, if I remember correctly, it's more active in stem cells than in somatic cells, for the most part?
Elissa: Yeah, so at UCSF, my colleagues, Jue Lin actually has an assay. It's very sensitive and can measure the level of telomerase in our normal blood cells. They're not cancerous, they're not stem cells, but you can still measure the level. And that is associated with health, with metabolic health, with socioeconomic circumstances.
A test used in laboratory medicine, pharmacology, environmental biology, and molecular biology to determine the content or quality of specific components.
Two nitrogen-containing molecules (called nucleotides) that form the "rungs" of the ladder-like structure of DNA. The DNA in a single chromosome contains approximately 150 million base pairs. The number of base pairs within the telomere region of chromosomes are of particular relevance to the field of aging. The length of telomeres, distinct structures comprised of short, repetitive sequences of DNA located on the ends of chromosomes, ranges from 8,000 base pairs in a newborn to 3,000 base pairs in an adult and as low as 1,500 in elderly people. The average cell loses 30 to 200 base pairs from the ends of its telomeres each time it divides, contributing to (and serving as a marker of) aging.
A measurable substance in an organism that is indicative of some phenomenon such as disease, infection, or environmental exposure.
A tightly coiled molecule of DNA found in the nucleus of a cell. Chromosomes contain the genes and other genetic material for an organism. Humans have 46 chromosomes arranged in 23 pairs. Each chromosome is comprised of long stretches of DNA wrapped around proteins called histones, which provide structural support. At the end of each chromosome is a repetitive nucleotide sequence called a telomere. Telomeres form a protective “cap” – a sort of disposable buffer that gradually shortens with age – that prevents chromosomes from losing genes or sticking to other chromosomes during cell division.
A double-stranded molecule that carries the genetic material for an organism. Each strand of DNA is composed of nucleotides strung together by covalent bonds. Nucleotides are typically identified by the first letter of their base names: adenine (A), cytosine (C), guanine (G), and thymine (T). They form specific pairs (A with T, and G with C) via hydrogen bonds, which in turn provide the helical structure of the DNA strand. Specific sequences of the nucleotides comprise genes.
DNA is packaged around histone proteins in units referred to as nucleosomes. Each nucleosome contains 147 base pairs of DNA. Complexes of DNA, RNA, and histone proteins comprise chromatin. Chromatin’s primary function is to compress the DNA into a compact structure that can fit within the nucleus. Chromatin structure and DNA accessibility can be altered by epigenetic modifications, or “tags,” such as DNA methylation and histone modification. Epigenetic changes, which do not alter the overall sequence of DNA, are heritable and can regulate patterns of gene expression.
Any of a group of complex proteins or conjugated proteins that are produced by living cells and act as catalyst in specific biochemical reactions.
A small organ located within the brain's medial temporal lobe. The hippocampus is associated primarily with memory (in particular, the consolidation of short-term memories to long-term memories), learning, and spatial navigation. Amyloid-beta plaque accumulation, tau tangle formation, and subsequent atrophy in the hippocampus are early indicators of Alzheimer’s disease.
Undifferentiated descendants of stem cells. Unlike stem cells, progenitor cells can differentiate into cells of a particular lineage only and they cannot divide and reproduce indefinitely. Progenitor cells show potential in the fields of plastic and reconstructive surgery, ophthalmology, and heart and blood disorders.
An enzyme that facilitates the generation of complementary DNA. In viruses, reverse transcriptases convert viral RNA into a complementary DNA, which can then be integrated into the host’s genome. In humans, the reverse transcriptase telomerase maintains and extends the length of telomeres.
A molecule that participates in the flow of genetic information from DNA into proteins.
Senescence is a response to stress in which damaged cells suspend normal growth and metabolism. While senescence is vital for embryonic development, wound healing, and cancer immunity, accumulation of senescent cells causes increases inflammation and participates in the phenotype of aging.
Any type of cell that comprises an organism’s body. Somatic cells do not include gametes (sperm or egg), germ cells (cells that go on to become gametes), or stem cells.
A cell that has the potential to develop into different types of cells in the body. Stem cells are undifferentiated, so they cannot do specific functions in the body. Instead, they have the potential to become specialized cells, such as muscle cells, blood cells, and brain cells. As such, they serve as a repair system for the body. Stem cells can divide and renew themselves over a long time. In 2006, scientists reverted somatic cells into stem cells by introducing Oct4, Sox2, Klf4, and cMyc (OSKM), known as Yamanaka factors.[1]
- ^ Takahashi, Kazutoshi; Yamanaka, Shinya (2006). Induction Of Pluripotent Stem Cells From Mouse Embryonic And Adult Fibroblast Cultures By Defined Factors Cell 126, 4.
An enzyme that extends the telomeres of chromosomes. Telomerase adds specific nucleotide sequences to the ends of existing chromosomes. Telomerase activity is highly regulated during development, and its activity is at an almost undetectable level of activity in fully developed cells. This lack of activity causes the cell to age. If telomerase is activated in a cell, the cell will continue to grow and divide, or become "immortal," which is important to both aging and cancer. Telomerase enzyme activity has been detected in more than 90 percent of human cancers.
Distinctive structures comprised of short, repetitive sequences of DNA located on the ends of chromosomes. Telomeres form a protective “cap” – a sort of disposable buffer that gradually shortens with age – that prevents chromosomes from losing genes or sticking to other chromosomes during cell division. When the telomeres on a cell’s chromosomes get too short, the chromosome reaches a “critical length,” and the cell stops dividing (senescence) or dies (apoptosis). Telomeres are replenished by the enzyme telomerase, a reverse transcriptase.
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Telomeres News
- Aerobic exercise (120 minutes per week) significantly lengthened telomeres, a biomarker for healthy aging, in white blood cells after 24 weeks.
- Coal plant emissions may be damaging infant DNA. Babies born during a coal plant’s operation in China had shorter telomeres.
- High physical activity levels were associated with delayed biological aging by 9 years as measured by telomere length.
- Air pollution linked to shorter telomeres, a marker for health & aging, in adolescents in a dose-dependent manner.
- High levels of exercise, equal to 30-40 minutes of jogging per day 5 days per week, linked to nine years of less aging at the cellular level.
