Structural Features of DNA Differ Between Short-Lived Rats and Long-Lived Blind Mole Rats
Which gene sequences are actively read by transcription machinery in the cell nucleus to produce RNA (some of which is then translated into proteins) is determined by the structure of nuclear DNA. The various assemblies of proteins making up that transcription machinery will read whatever sequence they can attach to. Regions of nuclear DNA can be packaged away and tightly furled, made inaccessible, or otherwise become accessible for a time through alterations to histone proteins, methylation of specific sites on the genome, and other strategies. All of this changes constantly in response to circumstances, many dynamic feedback loops of RNA and protein production and structural change to DNA all interacting with one another.
In today's open access paper, researchers offer a view of DNA structure that is less commonly discussed in the context of aging and longevity. This view emerges from the use of spectroscopy, which can be employed to gain insight into different structural variants of DNA. The double helix structure familiar to laypeople is known as B-DNA, but A-DNA and Z-DNA also exist. Spectroscopy can further can be used to visualize a range of small-scale features in the chemical structure of DNA, such as sugar puckers. Evidently, however one looks at DNA and gene expression, one is going to see differences between short-lived rodents and long-lived rodents.
What can be done with this information? At present very little. As is the case for epigenetic measures, there is no bridge of cause and consequence yet built to link specific structural DNA changes and specific forms of damage and dysfunction in aging. So one can measure structural differences across life spans within species and between species of different life spans, but it doesn't yet much help in the matter of how to build effective rejuvenation therapies.
The structural architecture of DNA, extending beyond its sequence-dependent genetic code, has emerged as a critical determinant of genomic stability, cellular function, and organismal longevity. B-DNA, which has a right-handed double helix structure with Watson-Crick base pairing, can form non-B DNA structures such as hairpins, triplexes, cruciform, left-handed Z-forms, G-quadruplexes, and A-motifs under specific conditions. While canonical B-form DNA represents the classical double-helical structure, dynamic conformational shifts, such as transitions to A-DNS or Z-DNA alter biochemical properties like flexibility, stability, and protein interactions, with profound implications for aging and disease.
Structural changes, such as the transition from B-DNA to A-DNA, influence DNA stability and flexibility and are affected by factors like DNA methylation and sugar puckering. This study is the first to investigate the relationship between DNA conformational changes and lifespan in two rodent species. The analysis focused on long-lived Anatolian blind mole-rat (Nannospalax xanthodon) and shorter-lived rat (Rattus rattus), utilizing infrared spectroscopy and principal component analysis (PCA) to examine liver DNA.
Results indicated that transitions from B-form to A-form and Z-form were more prevalent in N. xanthodon than in R. rattus. However, the dominant DNA conformations in both species are in B-form. Additionally, N-type sugar puckers (C3-endo conformation), associated with these DNA forms, were more prominent in N. xanthodon. In contrast, S-type sugar puckers (C2-endo conformation), characteristic of B-DNA, were found at lower levels in N. xanthodon. Furthermore, variations in methylation-specific structural modifications of nucleobases were quantitatively assessed among these species.
The study proposes a significant connection between the long lifespan of N. xanthodon, which live underground, and their unique DNA structure, offering insights into how different DNA forms, as well as the conformations of their backbone and sugar-base components, may affect longevity, highlighting potential research avenues regarding the biomolecular aspects of aging.
Hi! I'm in my 40s and I have to say, I am dismayed by the (quasi?non-existent? progress in biomedical/bio-gerontology science--advancing our understand of the human aging process) lack of advancement(small rant)..i.e. Mr. DeGrey...is getting more Gray (hair)....not getting any younger. You and him, both British blonde dudes in your 50s (both, living in USA..strangely), like your twin ..am blonde too (more dark blond); thankfully, since am still in 40s, no gray hair yet; but, I fear that (I shouldn't) that soon, my beard will turn grey 'salt&pepper' look...too. I cut it out, and thus, it does not show. Some people do not have any grey hair -- up to their 80s almost...but they are the minority; most get grey hair...by their 90s..and much earlier; some people, my age, in mid-40s...have grey hair, already. It won't look good----later; with a Full Grey Hair Head. Gray hair are a manifestation of oxidative stress in the follicule; ROS oxidizing free radicals excess in hair..and, most likely too, advanced 'epigenetic'/premature-aging ..in the follicule/ melanocytes...the 'pigments' for the hair (giving its color); the follicule cannot produce the melanin/pigments correctly/necessary to give the hair's natural color--it turns to grey; as it accumulates damage/is oxidative stressed (by ROS in it). Keeping your hair...not grey, is a good sign; but, not the entire explanation. As, it was demonstrated that organs don't age, exactly, at the same speed; but, Overall, skin condition/look is a good (surrogate) 'marker'/correlator of the Overall' age of the body, when tallying the organs' ages. It corresponds to other organs' epi-age also. Again, overall/averaging. There will be discrepancies though. It's why you may see someone 90 years old..with blond hair...or brown hair...when you would think, by that latest age/end-stage of life...they unconditionally...have grey hair. But, not always; and when they don't; you know they keep their body younger (like Centenarians, do; blessed with the genetics lottery jackpot at birth); scientists used to say...genetics has no impact or little....now, we're back to square1; genetics Absolutely have an impact in longevity (especially around the 9th decade of life); it is the difference between reaching 90...vs 115..... and; Of Course; you need to have all your bases... covered (i.e.: eat well, a good diet (mediterranean with fruits/veggies. like vegetarians), exercise, do Calorie Restriction (intermittent)/fasting/skip food portions..(which, is, yes - forced starvation; but, if you are 'filled/sasiated'..it does not feel like so; because you slow down the digestion/you're full/energy sufficient (as the stomach/intestines slowly grinds/absorbs whatever you put in it)..and then, you (end up) doing 'fast-ing'). I am saddened that the last 5 years are so 'barren' in terms of scientific discoveries about human biological aging; it's, just, notthing we don't know, already (it keeps repeating itself; like parrot; redundance); the fact you can see (stilll...) researches on calorie restriction or other means like...that; is why, we stall. Are stalled. As if, we are stuck on 'Gear 1' or, worse, 'P (Parking)' 'on place'...of a manual transmission-car; we can't reach 'Gear 5'.....to accelerate things. Whenever I read a new paper, it says: ''There is more to discover and explore..'' at the end; then, I weep, knowing that 'By The Time'...we 'make something'...it will be too late. The old saying: ''Not in your Lifetime''. ..won't happen...in your lifetime. Because, it takes---a lifetime...to even advance...a single step. We should have a Mouse that is Quasi-Immortal --By Now...but, no/nope. What do have/got...we have/got...more calorie restriction, 'health improving' (and f...aging, now seen hopeless pursuit); healthy aging' (my favorite misnomer/oxymoron); a big Façade/Illusion/Delusion....that, scientists are saying:...forget it; you'll die and that's it that's all (to it); being on the safe side, I understand that reasoning. But, that is, exactly, how will we assure, our (assured) death. Many new discoveries end up 'canned'...and that's sad; like, they might reverse epigenetic age in a mouse...but, there is little or no, concern of actual 'aging'...or rather, there is a concern, but it is now a Lesser concern; health primes; healthy aging, that is. So you can forget about living 150..ain't happening; there is, still, less than 10% of people on Earth who reach 110 years.
90% or more....do not make it to the big 100. So how many years of life you got left?...or 'Healthy' years...not decripiiting/in pain (of course). SENS therapies might make people reach 120 years lifespan...but even that, is not assured. We are 'rigged' for 120-130-140 years max rough-ly...thanks' to our telomeres/telomeric DNA dwindling. Telomerase, antioxidants, stem cell injection, epigenetic 'partial' reprogramming of induced pluripotent adult stem cells and the list goes on....none of them make us live past/above 120 years or so. The limit is Quite Hard. The Hayflick Limit (cell divisions/population doublings -> p53, p16, p21 tumor oncogenes appear...trying to thwarth cancer formation...or rogue cells 'immortalizing' (via tumor hijacking telomerase for theirselves))). Replicative Senescence. We can't overcome that if our telomeres drop to nothing. At 115 years old, your immune system's leukocytes telomeres are short..and your death is soon, immunosenescence will happen in the next 10 years or less. Cancer may take over and beat the (weakened/old) immune system's 'detection capability' of foreing bodies (pathogens, virus, ...and cancer/tumors)/antibody tagging'. The only way, in my POV, is to attack at the source, but so far, we can't reach/do it/that...I mean, attacking the Largest Contributor (reason)...why we age...and that's (in) the Mitochondria; the cell's energy-ATP producers. ROS, oxidative stress, reactive oxygen species (ROS) are massively present in it/them. Humans have a total of a quadrillion of them; this, is impossible to stop with age. Mitochondrias, faltering wit age, cause our death. If they falter faster, we die faster too/evidently. This will cause the demise of our nuclear DNA/telomeres once more; they will fray, and shorten rapidly; telomere attrition rate = longevity; mitochondrial ROS rate = longevity. Why do studies continuously search around; when the answer is right there..is it our incapability to fix the d*mn dna, the telomeres, the mitos...if we can't fix that...you can forget living 500 years or even, a 1000 y. 2 studies proved it; a ''A heart that beats for 500 years''; and ''Lifestyle in the longest-living metazoan animal on earth, the islandica arctica mollusk/bivalve oyster clam''. Essentially, it was demonstrated in this oyster, that -in order- to live 500 years...you must keep your Telomeres high...never drop...a 500 year old oyster's mantle, pedal foot, flesh/cartilage and heart demonstrated that around 30 years old, the oyster reaches maturity...telomeres drop..but then, telomeres/telomeric DNA Rise Up (like telomerase doing telomere extension/lengthening); and, for 500 years, the oyster never loses much any telomeres....to, reach, 400-500 years old. Demosntrating, that only if you keep your body 'young' (with high telomeres) do you reach several* centuries lifespan. Of course, in human, we get cancer..that's another kettle to fix...oysters also get cancer, but the ones that lived 500...pushed it the farthest and had the least amount of cancers/tumors when they checked. Meaning, it is Possible to thawrth cancer --and-- live half-a-millenia. But, so far, all the studies are mostly useless (At that, point); because, they do not target the major cause of aging (mtROS/Quadrillions of mitos (dysfunctional) killing us...slowly, but surely;`by their sheer numbers; making our telomeres shrink..and towards are death -- by replicative senescence).