The Extraordinary Longevity of Salamanders
An impressive regenerative capacity often goes hand in hand with longevity. Salamanders are capable of regrowth of lost limbs and injured internal organs, and are unusually long-lived for their size. Like other smaller species that exhibit an exceptional life span, salamanders are the subject of research initiatives that aim to find the relevant biochemical differences that produce greater species longevity. Additionally, scientists are very interested in understanding the specific mechanistic differences between mammals, largely incapable of regeneration without scarring, and species such as salamanders that are capable of scarless regeneration.
More inroads have been made into the question of regeneration than the question of longevity, and it remains far too early to say whether or not there is anything in salamander biochemistry that can be adapted into therapies and safely applied to a mammal in order to lengthen life span. The genetics and cellular metabolism that underlies differences in species life span is a complex swamp of detail piled upon detail, poorly understood and poorly mapped. Progress is slow, as there are only so many researchers in this part of the field, and only so much funding.
Salamander Insights Into Ageing and Rejuvenation
A salient feature of salamander regeneration is its resilience. Urodele regenerative capacity does not decline with time, and most studies suggest it is not impaired by repetitive regeneration events. A landmark study tracked the process of lens regeneration over 16 years in Japanese newts, removing the lens from the same animals 18 times and allowing them to undergo regeneration. Remarkably, the resulting lenses were structurally identical to the original ones and expressed similar levels of lens-specific genes. Subsequent analysis revealed that the transcriptomes of young and old (19-times regenerated) lenses are nearly indistinguishable, showcasing the robustness of newt lens regeneration. Of note, by the end of the study the specimens were at least 30 years old, representing a geriatric population in this species. This provides an interesting contrast to the declines in regenerative capacities observed in most vertebrate contexts.
Additional studies indicate that repetitive amputations do not affect tail regenerative potential in the newt Triturus carnifex, as examined over a 10 year period with up to nine tail regeneration cycles, nor that of the axolotl limb, challenged by five regeneration rounds during 3 years. Taken together, the evidence to date suggests that the ability of urodeles to regenerate complex structures does not decline with time or serial regeneration cycles. In mammals, loss of regenerative potential with ageing has been largely attributed to the ageing of stem cell populations and/or their niche. Whether the prevalence of dedifferentiation as a regenerative mechanism in salamanders is linked to the indefinite nature of their regenerative potential remains an outstanding question.
Beyond their remarkable regenerative abilities, salamanders exhibit extraordinary longevity, constituting lifespan outliers with respect to organismal size. Among animal species, there is a notable correlation between body mass and lifespan, with larger animals living longer. Yet, salamanders break this rule by several orders of magnitude. For example, axolotls - average mass: 60-110g - live over 20 years, and cave olms - Proteus anguinus; average mass: 17g - can surpass 100 years. Indeed, they match and in some cases exceed the lifespan/body mass ratios found in other well-known outliers such as the naked mole rat and Brandt's bat. This is even more remarkable given that most salamander longevity data derive from specimens in the wild, where animals are exposed to environmental challenges, predation, pathogens, and food source fluctuations. Thus, salamanders are not only lifespan outliers, but also in many cases their longevity may be underestimated.
Hey there! Just a 2 cents.
This is really cool, and it is actually showing the parallels between 'negligeably senescent' animals, like NMRs (Naked Mole Rats) and Bats and..of course, humans (even if we are not 'negligeably senescent...we are quite not-senescent for a very long time too; it's why we can live longer than salamanders too - but not longer than quahogs or sharks or whales or jellyfish).
This, specific, salamander urodele is (specifically) special/unique; it is akin to the Axolotl (mexican-aztecan nahualt cave albino salamander) can regenerate its limbs (much like snakes or certain insects or other types of aquatic animals; and other salamanders types obviously).
It is the dedifferentiation (reversal back to former state/as if back to original limb structure)/its stem cells that allow it to have infiinite limb regeneration potential (so long as it has stem cell supply and/or capability for dedifferentiation). This means it has the genes working for it (that we don't (as adult)..or rather do we have them too but because of antagonistic pleiotropy they get turned off pretty quick (after early childhood/natal period)/are useless later (for us);
I believe this is due to the salamander having faced certain predators...and ? lost limbs...to them (when attacked as 'prey/menu/snack'). Because this specific salamander has basically no predators..from its destitute living environment - lifeless; akin to NMRs burrows, closed-in, isolated, sheltered and living a cloistered pitch black-cave life (like a cloistered monk/recluse or hermit; they lived long lives...because 'staying-in' and avoiding dangers outside/predators that lurk out there). Same thing to 'chimeras' in the deep abyss (scary looking 'angler-fish/lightbulb fish' in the pitch black of the abyss.
The way the salamander may have been 'snatched/eaten' may have given it the chance to 'evade' the mouth; by 'regrowing body/limbs'...regrowing itself...outside the mouth of predator. It would be genious, if a shark eats you in two...just regrow the part missing while it eats you. Escape. The shark will have your 'former self (part (of you)'...as souvenir (of you). But you are 'remade' so you don'T need your 'old you/part'.
This process could be quite fast, and not take days...not even hours...but a minute or second and 'Pop!'...a new 'organoid/limb/appendage' 'has been 'bioprinted'...(like bioprinted organoids).
Obviously, it's not that fast, it's very longer than that ('tail regeneration cycles (over years)).
It may also be a form of 'shedding' (like skin or nails or hair shedding/falling/peeling-off); as if 'renew(al/ing)' the parts was part of the body's 'daily maintenance'.
''Whether the prevalence of dedifferentiation as a regenerative mechanism in salamanders is linked to the indefinite nature of their regenerative potential remains an outstanding question''
It is linked, it's not a secret anymore, this animal is using stem cell/dedifferentiation processes to rebuild itself should it lose a part.
''Additional studies indicate that repetitive amputations do not affect tail regenerative potential in the newt Triturus carnifex, as examined over a 10 year period with up to nine tail regeneration cycles, nor that of the axolotl limb, challenged by five regeneration rounds during 3 years. Taken together, the evidence to date suggests that the ability of urodeles to regenerate complex structures does not decline with time or serial regeneration cycles. In mammals, loss of regenerative potential with ageing has been largely attributed to the ageing of stem cell populations and/or their niche.''
This is interesting, it means its stem cells are not facing replicative senescence and it has continuous access to important stem cell markers/cell dedifferentiation genes that are also important for stem cell renewal, this is the Yamanaka factors (NANOG, SOX, OCT, C-MYC), these genes are the ones that can reprogramming epigenome & are also in stem cells (epigenomes) and for limb regeneration or skin macrogranulation (scarless healing of injury wound in children). The limb/bone regeneration genes are also the Retinoic Acid genes (it was shown that retinoic acid/vitamin A genes have skeletal morphology control in birds; they are important to the sketelal/skeleton shape (wings) of birds and their skull/beak. Likewise, in humans, too.
''Among animal species, there is a notable correlation between body mass and lifespan, with larger animals living longer. Yet, salamanders break this rule by several orders of magnitude. For example, axolotls - average mass: 60-110g - live over 20 years, and cave olms - Proteus anguinus; average mass: 17g - can surpass 100 years. Indeed, they match and in some cases exceed the lifespan/body mass ratios found in other well-known outliers such as the naked mole rat and Brandt's bat''
True...but (mostly) only true (trend) - in Mammals. Not (really) in salamanders...nor NMRs, nor bats....
These are not mammals, and thus, why there is discordance/discrepancy
between mass/size vs longevity in these mini animals that live ultra-long lives.
In mammals, the overall trend stays...the bigger they are the Longer they live.
It was demonstrated that the reason for that is because larger bodies (in mammals) make for more 'cellularity' and this also 'slows down (cell) kinetics' (metabolism), thus, for example, by having more cellularity, they have more 'gene content' (per se); it was shown in bowhead whales (that live up to 268 years; the longest one found was estimated 211 years (by aspartic racemization/calculation dating of its eye len); but by epiclock they can live 268 years - almost 300 since there was a trend for 'underestimation' of epiage (modern h.sapiens humans, by epiage, were estimated to live 39 years, while Denisovans (ancient extinct cave humans) live 30 years or so using epigenetic clock measuring of their ancient DNA on their fossil bones; thus, the estimation may undermine the capability of humans to live longer; we don't just live 40 years anymore...we can reach 122; that's because humans push the limit - to the Very Limit over last 1000 years of evolving/improving health/longevity (120) (grand-mother theory/longevity genes from oldest grand-ma; maybe bowhead whale could reach 400-500; since Greenland sharks live 400 years that has been shown; nothing says a whale could not necessarily reach it too; thus, sometimes epiclock measuring could underestimate things (or overestimate?); but overall it is the most precise measuring right now for aging))); It was found that Bowhead whales, which are Gigantic in size, live nearly 250+ years...and have longer/bigger neural gene content...than other mammals. Thus, they are 'wired' better, they have more 'nerves' and most lkiely more neurons too...this neural genetic component means better impulse/communication over the entire body, if you communicate better/faster with organs you can do more/faster...and you need less 'effort' because there is just more 'connections' to begin with...it's like comparing a 5000 RPM vs 10,000 RPM engine...it goes without saying; the latter will force a lot less because spinning double-time.
This means that these ultra long-lived 'giant-sized' mammals like bowhead whales preserve organ function better and can slow their aging (better, too). Despite that the animal mammal is Gigantic in body/mass/size VS a mini salamander/mini rodent NMR/mini bat/mini animal (non-mammal) that lives 30-100 years....and measures less than your palm and weighs less than a
pocket tick-taks mints'box.
It means that body/size/mass vs Lifespan/longevity can be uncoupled, when not talking about mammals.
But When talking about mammals, this correlation stands (mostly) and thus,
Bigger Mammals = Bigger Lifespan.
Smaller Mammals = Smaller Lifespan.
''...This is even more remarkable given that most salamander longevity data derive from specimens in the wild, where animals are exposed to environmental challenges, predation, pathogens, and food source fluctuations. Thus, salamanders are not only lifespan outliers, but also in many cases their longevity may be underestimated.''
Yes, they are outliers...because are minuscule-sized..and live decades (thanks to cell/limb regeneration)...and
because of their Environment..or lack thereof. Their environment is 'barren'...a dark cave where it's constant pitch black dark
and it's 'Closed-in' (a cave), thus, like bats (living in cave ceilings), they are shielded from exterior predators since not
many are troglodytes (cave living animals), most live outside caves; animals that live in caves are isolated and face not many
dangers (from outside) since they, are, inside (a cave). Cloistered/sheltered - lifetime protection; like living in a bunker.
They can thus (afford to) live however long they wish and regenerate however many limbs and tails they fancy.
Just a 2 cents.
https://medicalxpress.com/news/2021-07-methylglyoxal-detoxification-deficits-schizophrenia-like-behavioral.html
"Methylglyoxal (MG) is a highly reactive α-ketoaldehyde formed endogenously as a byproduct of the glycolytic pathway. MG accumulates under conditions of hyperglycemia, impaired glucose metabolism, or oxidative stress. An excess of MG formation causes mitochondrial impairment and reactive oxygen species (ROS) production that further increases oxidative stress.
It also leads to the formation of advanced glycation end products (AGEs) due to MG reacting with proteins, DNA, and other biomolecules, which can induce aberrant inflammation via binding to receptors for AGEs (RAGE). To remove the toxic MG, various detoxification systems work together in vivo, including the glyoxalase system which enzymatically degrades MG using glyoxalase 1 (GLO1) and GLO2, and the MG scavenging system by vitamin B6 (VB6).
Schizophrenia is a heterogeneous psychiatric disorder characterized by positive symptoms, such as hallucinations and delusions, negative symptoms, such as anhedonia and flat affect, and cognitive impairment. A new study has reported that several patients with schizophrenia have a novel heterozygous frameshift and a single nucleotide variation (SNV) in GLO1 that results in reductions of enzymatic activity. Furthermore, the study reports that VB6 (pyridoxal) levels in peripheral blood of patients with schizophrenia are significantly lower than that of healthy controls. More than 35% of patients with schizophrenia have low levels of VB6 (clinically defined as male: < 6 ng/ml, female: < 4 ng/ml). However, the effects of MG detoxification deficits on the pathophysiology of schizophrenia in vivo remain unclear"
Posted as it's related to several things (e.g. AGEs) that get posted about often.
https://www.zerohedge.com/covid-19/why-covid-aids
"British researchers published a definitive paper on the subject in The Lancet Diabetes & Endocrinology, a peer-reviewed journal. The researchers examined the medical records of almost 7 million people in England to look at the link between obesity and severe outcomes from Covid, including hospitalization and death.
The topline findings show only a moderate link between extra weight and Covid risk. But when the researchers looked more closely, they found that's because in older people, being overweight does NOT drive excess risk.
So the researchers divided the patients into four age ranges: 20-39, 40-59, 60-79, and over 80. They found that in the two younger groups - including adults up to age 60 - being obese was associated with nearly ALL the risk that Covid would lead to intensive care or death. The findings held even after they adjusted for many different potential confounding factors, like smoking, non-weight-related illnesses, and wealth.
The excess risk was extremely high even for people who weren't morbidly obese - defined as a body-mass index of 40 or more. A person between 40 and 60 with a BMI of 35 - someone who is 230 pounds and 5'8" - had about five times the risk of dying of Covid of a person of normal weight. For younger adults, the excess risk was even higher, and for morbidly obese people even higher still.
In contrast, people of normal weight under 40 are at essentially no risk of death from Covid. The researchers found their rate to be under 1 in 10,000 per year. Even in the 40 to 59 age range, normal-weight adults had an annual risk well under 1 in 1,000."
It seems obesity causes premature aging, or at least being obese mimics being older.
@CANanonymity
It is not sufficient to say that our genes for regeneration have been switched off because of 'antagonistic pleiotropy' without stating what the disadvantage having such genes would be (for a mammal). Are they expensive? If they are, why have they not been eliminated in salamanders? Do they cause cancer? Again, we don't see this in Salamanders. Or is it just random, an evolutionary accident that mammals have had to make the best of...
Hi Mark! Thank you for that and asking. Just a 2 cents.
Good questions, I would wager that for the larger mammals, their predation would become less by their larger size (no predators since bigger than them), as such, they would not have an immediate need for constant limb replacement/regeneration...since they would not face any injuries/limb loss, because no dangers/no predators. As for smaller mammals, it could be very advantageous for them (it is not a random thing that salamanders are minuscule-sized and retain this regenerative potential; I mean you could have a salamander as big a bus or giant whale...but it would have very little predators by being so large; regeneration potential would then be moot/redundant/useless since it would not lose any limbs to any predators; because has no predators at that giant size). Small salamanders were definitely attacked sometimes and I don't know but it was probably very lethal or crippling (limb loss), it was not just some thing like that (nearly sure); there is likely an advantage to this. The fact that cave salamanders can live 30 to 100 years goes to show that it is an evolutive advantage; repairing/regenerating could be the 'Side Effect' of them living this long; like being able to regenerate so well/so much any part of their body...goes hand in hand with them living 100 years...it fuels their longevity (stem cell renewal; somatic tissue maintenance/rebuilding...and limb rebuilding too). For humans, we don't get 'limb eaten' but we live as long as these salamanders; we have few offpsrings and put more DNA resources towards somatic tissue maintenance and we push back puberty/having kids as late as possible; this is very close to what happens with NMRs (Naked Mole Rats) that live 35 years and have a Very protracted period to entering puberty (it's late...much later than mice, obviously, since it lives only 3-4 years), thus, humans, like NMRs and like salamanders, invest more into DNA repair/somatic tissue repair/maintenance/regeneration -> Longevity; -> Less children; -> Later Parenting.
I would say yes the genes for renewal/regeneration are expensive because this regeneration process is not costless (resource cost); that is what I am trying to get at; humans/NMRs/salamanders are putting their savings (resources) - for those regeneration/longevity genes (they overlap); and less so towards immediate/intense sexual reproduction (we can't pop a baby in 2 days); it was shown that sexual senescence is problematic for humans because sex hormones also have a say on lifespan (oestrogen and testosterone control telomerase (oestrogen activates telomerase receptors in brain; it's evolutive advantage women have with having DoubleXX (Double XX chromosomes) vs male Xy; and is why women living longer in general than men (in men testosterone is converted to oestrogen via aromatase enzyme - then it can do the same thing/activate TERT receptors and confer increased protection of chromosome telomeric DNA repeat, in men which means healthier/longer lifespan))) it is why menopause (women, oestrogen fall) and andropause (men, testosterone fall) cause sexual senescence and severe health problems (because telomerase lowers by sexhormonal reduction of age); in women, this can be cardiac failure (caused by menopause), while in men this can be (impotence, caused by loss of NO in vessels or damaged 'signal' to sex organ; this is very dangerous because it means endo vasculature damage -> cardiac failure/heart attack later; not just that if it falls, well TERT levels fall too - everywhere, and that means acceleration of telomere erosion in men; translated as accelerated biological/mitotic aging (it was found that regions of the telomeres/centromeres/subtelomeres are methylated; as they dwindle and 'loosen' they demethylate and the histones loosen/lost, this causes epigenomic disarray/advancement of the epiclock by loss 'gene silencing' (in essence, Tight telomeres are Tall and methylated; they 'change in conformation' as they shriken, it's not just 'size/height' - it's composition changes as it shortens; this causes epigenetic drifting and epiclock ticking forward).
Yes, the regenerative genes in salamanders can/and do cause cancer, because these genes (mainly Yamanaka) are highly 'stem-cell state'/proliferation/cell cycling inducing, they return aged/differentiated cells to their pluripotent state - very 'virgin/stem' cell with an epiclock age of 0; thus, cancers, highjack that and use that to their advantage...
But in salamanders, they developed mechanisms that stop metastatic/tumor formation from this rapid regeneration/call of these genes; for example, it was found that naked mole rats have cell 'Contact inhibition' and elephants had more copies of p53 tumor suppressor genes; thus, they counter someway; it is possible that salamander have 'stronger stromal barriers' that stop the tumor 'from spreading' to another organ (stromal cells block that), or has also a sort cell contant inhibition mechanism like in NMR that stops cancer dead in its track; it is possible they have moer tumor suppressor gene copies (p21, p53, p16...)l thus better cancer defense and also better immunity/immune cancer eradication (T-Cells/NK-natural killer cell/macrophages/white blood cells that phage tumors, better); it was shown that taller telomeres in leukocytes (white blood cells of immune system) it was a good indicator of better/stronger immunity; salamanders have pristine body/skin..negligeably senescent, they have tall telomeres and low telomere erosion rate (otherwise they would live no longer than a mouse;
Mouse -> 5000 DNA basepair/per year lost (they have 50,000 DNA basepairs long telomeres and live 3-4 years; the long telomeres just stave off the extreme loss per year)
Salamander -> 50 DNA basepair/per year lost (they thus can live 100 years, even if their telomeres are smaller; they just lose 100x times less/year).
Studies said that Tall Enough was important, but what was More Important is the Rate of Telomere Erosion and the Number of New Smallest Telomeres (in the total bunch); that dictated the lifespan whether the animal 50Kbp long telomeres or 10Kpb smaller telomeres; it's how fast they dwindled each year that determined the lifespan, not their initial/overal length/size.
Still, having taller telomeres is better (even mouse that obtain TERT had Longer Telomeres and lived longer - and I think their telomere shortening rate was slightly less..but overall not that much I mean..they still died in less than 5 years...but that goes to show..not the length; but the speed of shortening).
Just a 2 cents.
I'd say that there's just a lack of selective pressure to maintain it in mammals. When a mammal loses a limb, they're almost certainly going to bleed to death - being warm blooded, the minimum oxygen demand of tissues is quite high, and as such, lowering blood pressure to the levels necessary to prevent exsanguination is just going to result in fatal hypoxia instead. So if an organism is going to die very soon after losing a limb, it doesn't matter if they can regenerate or not, they're not going to live long enough for that to be relevant, and as such any mutations that damage genes responsible for regulating regeneration aren't going to be selected against much at all. Contrast with ectotherms, which by lowering their body temperature are able to reduce their oxygen demands to very low levels indeed, and as such they are much more likely to be able to reduce their blood pressure enough to prevent exsanguination without causing fatal hypoxia in their tissues. As such, they have a much more realistic chance of surviving the initial injury long enough for the presence or absence of regenerative ability to actually come into play.
Hi Arcanyn! Thanks for that, that's a solid explanation. Just a 2 cents.
For many animals, mostly liklely, as you said limb loss is fatal; but it,s possible some survive this (as you mentioned with ectotherms going hypothermic/slow metab to counter oxygen demand (at severed limb location)/minimize effect of blood loss/hemoglobin loss making hypoxia (by blood loss) and make low blood oxygen/pressure possible)..yes of course this much worse for warm blooded mammals than cold blooded animals by our high temperature/O2 need making slowed metabism/lowered temperature to make hypoxia possible (when we need high O2 for organ function/have higher blood pressure/faster metabolism by higher metabolic temperature), a problem.
Salamanders (fall in the/)make me think of the geckos, small lizards, snake, serpent or...reptiles (cold-blooded metab, iguanas), they can hibernate, and salamanders can even regenerate limbs; they are related/linked (distant relatives, thus share these capabilities (slow metab, low body temp, regenerate limb.s, ;live for decades...).
Just a 2 cents.