Time changes us, even in our DNA. That’s how

Article by Priscilla Biswas Deputy Scientific Director di SoLongevity
Over time our DNA changes: it progressively accumulates small damages, called mutations, which are part of the aging process.Increased genomic instability (namely the frequency of this damage to the genetic material) can lead to the development of cancer and some chronic degenerative diseases.Many factors contribute to the accumulation of DNA damage and are both exogenous, such as chemicals or ionizing radiation, and endogenous, for example free oxygen radicals (ROS) or random errors in the DNA replication process.Fortunately, most living organisms, including us, are equipped with DNA repair mechanisms, but as they age they become inefficient.

What does DNA look like?

DNA, or deoxyribonucleic acid, is the material that collects all the information, “packaged” in genes, related to a living being. It is like a recipe book, where each recipe serves to create the proteins that make up the organism and allow it to function.From a chemical point of view DNA is a polymer, a macromolecule that is composed of four different monomers. Each monomer, which is called nucleotide, consists of a phosphate group, a sugar molecule (deoxyribose) and a nitrogen base (adenine, thymine, cytosine or guanine). The monomers join together to form a DNA chain (or filament).DNA is a macromolecule composed of two complementary strands of nucleotides that wrap around each other to form a double helixIn fact, most of the DNA present in our cells is double-stranded: two polynucleotide chains join together by affinity of nitrogen bases that form adenine-thymin and guanine-cytosine pairs.We can imagine the double-stranded DNA molecule as a ladder, in which the scaffold is made up of sugar molecules and phosphate groups, while the rungs are the nitrogen bases. This molecule then wraps around itself to form the famous double helix of DNA.[In the nucleus of human cells, DNA is well organized and when the cell divides it thickens to form chromosomes]In a human cell, DNA is contained in the nucleus, a compartment separated from the cytoplasm by the nuclear membrane. Here the DNA takes on a complex organization: the double filament is rolled up on protein complexes called histones (a structure similar to a pearl necklace), and then further wrapped into chromatin.In the nucleus the chromatin is not piled up at random but is organized by a precise architecture of fibrous proteins (lamìne) which form the nuclear lamina, associated with the internal nuclear membrane. When the cell divides (mitosis) the chromatin thickens even more to form the chromosomes.
DNA interacts with numerous protein complexes to form chromatin, which during mitosis further compacts to form chromosomes.

What causes genomic instability

When DNA replicates, mistakes can happen. This small amount of inefficiency (one wrong base every 109 duplicate bases) is not necessarily negative for the cell: it is also one of the forces that drive the evolution of every living species.Genomic instability is the phenomenon that causes alterations in the genetic make-up of a cell.As anticipated, however, there are also many other factors, both internal and external, that cause damage to DNA. One of the internal (endogenous) factors is the action of free radicals, or namely reactive oxygen species (ROS), molecules produced as side effect of oxygen metabolism (i.e. cellular respiration) that are unstable and tend to react with other molecules by breaking chemical bonds. External agents (exogenous), instead, include harmful chemicals, pollutants, ionizing radiation, smoke, etc.. In short, whatever the causes, DNA is subject to a certain degree of instability.

How the DNA repairs itself

DNA damages are not all the same. There may be, for example, mismatches between bases (guanine-adenine or cytosine-thamine), adduct formation (a T-T pair in the same filament), damage to nitrogenous bases, insertions, duplications and deletions of bases, double helix breakage, and more. DNA repair mechanisms use enzymes that recognize the damage, correct it and stitch the double strand together.Fortunately, living organisms have developed sophisticated mechanisms for repairing DNA damage, which use the function of various enzymes, such as proteins that mediate specific biological activities.For example, in the case of a damaged adduct or base, that altered piece of DNA is first recognized, then cut and finally repaired. In the process of DNA repair, sirtuins play an important role, these valuable molecules are involved in maintaining the well-being of the body on several frontsSirtuins, NAD-dependent enzymes also known as anti-aging proteins, play an important role in the DNA repair process. These valuable molecules are involved in maintaining the well-being of the body on several fronts. Experimental deletion of sirtuins in animals is associated with higher risk of developing type 2 diabetes or metabolic syndrome, but also alterations in cardiac function and circadian rythm.In mice without sirtuin 6, in particular, degenerative processes associated with aging (progeroid symptoms) develop prematurely.Research has discovered that sirtuin 6 is associated with chromatin and promotes DNA resistance to damage, suppressing genomic instability; moreover, it seems to influence the activity of some transcription factors (proteins that read the code of nitrogenous bases of DNA converting it into RNA, from which proteins will be synthesized) and therefore the expression of genes related to cellular aging (such as those for survival, senescence, inflammation and immunity).Over time, cells lose the ability to repair DNA: increased genomic instability can cause functional damage and oncogenesis.Over time, however, cells lose the ability to repair DNA and the physiological increase in mutations can cause significant functional damage to cells until cancer.

Aging and telomeres shortening

DNA damage occurs almost randomly, but there are some parts of the genome that are more sensitive. Examples are telomeres (from the Greek telos, i.e. fine, and meros, i.e. part), which are single helix DNA structures that hold the ends of chromosomes, mantaining  their unicity and stability.Telomeres are replicated by a particular enzyme called telomerase, that is lacking in many somatic cells. For this reason, with advancing age each time the cells divide, the telomeres become shorter and shorter.When studying this phenomenon, a strong correlation between telomere length and lifespan has been observed: the shorter the telomeres, the higher the mortality rate. The discovery of the association between telomere shortening and aging won the Nobel Prize for Medicine and Physiology to Australian biochemist Elizabeth Blackburn in 2009.The cell does not have telomere repair mechanisms; on the contrary, they are linked to a multi-proteic complex, called “shelter-in“, which protects them from DNA repair systems. In fact the telomeres, being single helix, would be recognized as DNA breakage and if they were repaired there would be a fusion of the various chromosomes, with very serious damage to the organism. Mutations in shelterin proteins are found in some cases of aplastic anemia and congenital dyskeratosis.‍There is a strong correlation between telomere length and lifespan, as demonstrated by the studies of Nobel prize winner Elizabeth Blackburn‍Another part of the genome most susceptible to damage is mitochondrial DNA (mtDNA), the genetic material contained in the mitochondria, the energy centres of cells. This DNA, single helix and not associated to histones, is particularly exposed to the action of free radicals that are produced in quantity in the mitochondria. Moreover, mtDNA repair systems are less efficient than those of nuclear DNA.
Progeroid syndromes are rare genetic conditions caused by the alteration of genes involved in the mechanisms that regulate aging, which appears early.

Progeroid syndromes

As it often happens, much of what we know about aging comes from the study of progeroid syndromes, very rare conditions caused by the alteration of the molecular mechanisms that govern aging. Individuals with progeroid syndromes show symptoms of accelerated aging that  affect many (but not all) organs and tissues.Werner’s, Bloom’s, Cockayne’s, Seckel’s, xeroderma pigmentose and trichotheodystrophy, for example, are genetic diseases caused by mutations that make DNA repair mechanisms inefficient.Much of what we know about the molecular mechanisms that regulate the aging of the body comes from the study of rare genetic conditions called progeroid syndromes.Genetic mutations of nuclear lamina proteins, on the other hand, are the cause of accelerated aging in the progeroid syndromes of Hutchinson-Gilford and Néstor-Guillermo.congenital dyskeratosis and Hoyeraal-Hreidarsson syndrome, then, are monogenic diseases caused by mutations in the genes that encode for the components of the telomerase complex, the enzyme that allows the replication of telomeres.For this reason, patients have alterations in the mechanisms of regulation and maintenance of telomere length, which manifest themselves with skin problems, bone marrow dysfunction, predisposition to tumors, hair loss and early osteoporosis.

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