Gain and Loss of Flight as a Tool to Search for Important Factors in Longevity

The capacity for flight is frequently associated with greater species longevity, such as in bats, for example. The present consensus suggests that the cellular adaptations needed to support the greater metabolic capacity required for flight also resist some forms of molecular damage important in aging. This is particularly the case for adaptations in mitochondria, the power plants of cells, where damage and loss of function is known to be important in aging. The membrane pacemaker hypothesis is one way of looking at this; species that evolve cell membranes that are more resilient to oxidative damage will live longer as a result.

Today's open access paper reports on the interesting approach of using gain and loss of flight in evolutionary history as a way to look for genes and functions that might be important in aging. It is a good idea, but unfortunately didn't pan out in this particular study - commonalities between species were lacking. That a modest selection of species failed to produce shared genetic adaptations that appear relevant to aging and longevity may indicate the existence of broad a diversity of mechanisms relevant to metabolism and flight, rather than just a few important mechanisms, or perhaps a very complex, multifaceted relationship between metabolism and longevity. Other lines of work, such as the so far largely unsuccessful search for longevity-related genes with meaningful effect sizes in humans, support the latter conjecture.

Genetic factors for short life span associated with evolution of the loss of flight ability

Maximum life span (MLS) is a fundamental life-history trait related to the rate of aging and senescence in animals. It has been proposed that species with lower extrinsic mortalities have longer life spans because they can invest in long-term survival. Extrinsic mortality is generally determined by ecological factors, such as climate and predation risk, and may drive shortened or extended life spans through natural selection. However, MLS is influenced by complex molecular and metabolic processes such as mitochondrial homeostasis.

Mitochondria of aerobic animals produce reactive oxygen species (ROS), which can damage lipids, proteins, and nucleic acids. A low rate of mitochondrial ROS generation reportedly leads to long life spans in both long-lived and calorie-restricted animals because of low levels of both oxidative stress and accumulation of mutations in somatic mitochondrial DNA. Because animals with higher metabolic rates produce more ROS, a causal relationship between metabolic rate and life span can be expected. Additionally, a positive relationship between body mass and life span is pervasive in vertebrates. Because metabolic rates per mass are lower with increasing body mass, animals with smaller body masses could suffer more from ROS, and their life spans would be correspondingly shorter.

However, flight ability significantly affects MLS and aging rates in both mammals and birds regardless of body mass. Flight typically requires higher rates of energy consumption and generates more ROS than other types of locomotion, such as walking or swimming. However, a prolonged life span often evolved with the acquisition of flight ability, suggesting that there is no simple relationship between metabolism and life span.

Here, we examine the parallel evolution of flight in mammals and birds and investigate positively selected genes at branches where either the acquisition (in little brown bats and large flying foxes) or loss (in Adélie penguins, emperor penguins, common ostriches, emus, great spotted kiwis, little spotted kiwis, okarito brown kiwis, greater rheas, lesser rheas, and cassowaries) of flight abilities occurred. Although we found no shared genes under selection among all the branches of interest, 7 genes were found to be positively selected in 2 of the branches. Among the 7 genes, only IGF2BP2 is known to affect both life span and energy expenditure. The positively selected mutations detected in IGF2BP2 likely affected the functionality of the encoded protein. IGF2BP2, which has been reported to simultaneously prolong life span and increase energy expenditure, could be responsible for the evolution of shortened MLS associated with the loss of flying ability.


"Because animals with higher metabolic rates produce more ROS, a causal relationship between metabolic rate and life span can be expected..."
I suspect that allowing for more or less ROS is simply one of the many ways a species lifespan is adjusted (programmed) by selection (evolution). In other words, relative ROS is more of an effect than a cause, and can be managed in various ways to influence lifespan. The ultimate "cause" of aging (i.e., "why do we age at an exponential rate, ensuring a timely death?") are factors external to the species, in particular competition with other species, and with evolution being perfectly capable of creating short- or long-lived flying animals of varying size.

Posted by: dtkamp at July 17th, 2020 9:42 PM

Hi there! Just a 2 cents.

My take is that most flying birds/bats/aviary and flying mammals evolved to be fit/efficient for flight; while flightless birds/animals, less so; because no need anymore. A hummingbird can flap its wings thousands of times in seconds...its heart beats at 1000-5000 bpm (beats per minute) during stationary non-moving 'levitation' flight, while its wings flap at extreme speed/in a total blur; it lives about as long as a mouse; 3-5 years; a mouse's heart beat is 700 bpm; birds are able to offset extreme flight muscle activity/demand by night torpor/slowed metabolism. As such, a hummingbird might be 5000 bpm in day flight; and at night, in torpor, down to 100 bpm; the average of all of this; is about the mouse'S heart rate - 700 bpm. And, why, they live the same lifespan. Despite a much faster heart rate/metabolism (for flight) but bird compensates by daily torpors/self-slowed metabolism; which makes an average of the same for both (and hence why they live roughly same longevity).

It is a bit like self-imposed anoxic mud-burying (like clams) or hibernation in bears/squirrels/snakes/toads/frogs in deep freeze winter...they produce anti-freeze liquid in their liver (that moves systemicallly via blood all over vasculature/organs) which protects against ice crystal formation; which would rupture their tissues/cells (in freezing temperature/if their tissues freeze/form into ice). Same thing with bats, (little brown bats/myotis) bats also live 40+ years old and are small/thin, very efficient body for flight and they Too also do 'upside down' torpor (just go check in a cave...bats are there..sleeping/in torpor/low metabolism..'hanging upside down' on the ceilling). Their flight makes high beats per minute of heart/high metabolistic load/need; but they stop and 'rest' like birds, and slow down to a crawl their metabolism; hence, the 'average' of this is overall not so high bpm (Even if they do High Heart Bpm Flight). Birds, bats, and other fliying animals have special adaptations; and they were shown to have higher bilirubin/bile fluids; thus strong antioxidation (more of it; to counter wing muscle ROS elevation during flight activity/motion); daily torpor (reduce metabolism/Reduce metabolism ROS); bats had better proteasome/proteo-phagic capability/autophagy/mitophagy...they clear out junk better and they have more Chaperones/lyso junk docking activity (HSF/HSP/LAMP...); also better nuclear response/antioxidation/redox priming (NRF2); mitomembrane that are resistant (they may have more linoleic acid or EPA/DHA; they preserve fluidity while keeping Peroxidation Index low overall/they protect their membranes with redox glutathione/antiox. systems); thus, overall they keep low ROS. I'll repeat they Keep low ROS; animals that age too quick do not Keep low ROS; ROS RISE with age. ROS are important, for they are the element that make the telomere shrink; faster ROS / faster telomere shrinking.

It's why the redox has been in high selection pressure; to try to mitigage ROS by scavenging them (SOD/CAT/GSH/GST/ASC/ TOCOPH/THIOREDOX..); when these antioxidant systems are depleted, you can see the cells die rapidly because no more protection against ROS. With age, the redox is oxidized and ROS takeover/rise; until the Tipping point; tipping balance between Antioxidation and Oxidation, is tipped towards Over(t)-Oxidation. That's when ROS will supplant the Anti-ROS systems. And telomeres will accelerate; and this will show down the epigenome (with faster demethylation of it/loss of cystonines); while histones will be lost, and progerin/lipofuscin/ALEs/AGEs... will accelerate dramatically.

External factors definitely 'shape' why an animal lives longer or less; but, these mechanisms are Required to reach hayflick/telomere shortening; ROS are Necessary/essential for that; it's why when cells are put to low O2/hypoxia/anoxia - there is less Oxygen - less Reactive *Oxygen* Species (ROS). Because less oxygen molecules; so less ROS. Animals/evolution understood that and it is why clams bury themselves in the seabed mud/in full anoxia/hermetism (total absence of oxygen) for weeks on end and they heart beats at 1-5 beats per minute; that is 10-50 times slower heart rate than humans; that means dramatically less ROS because ultra slow metabolism. Humans are lucky to live 122 despite our fast body/metabolism; we pushed the 'antioxidation' systems at maximal possible; a bit like supercentenarian ara blue parrot birds of amazonia that live 111 years old or an albatros bird that lives 40 years and has telomere elongation with age (albeit albatros are dubious/ambigious; studies on them are mysterious; their telomeres lengthen with age; but it makes no difference, by telomere shrikning rate they still lose about 300 bp/year...hence live about 30 years; and also, predation, they may be 'snuffed out' of the population too quickly; and if lab raised they might live as long as the ara bird; If they reduce their telomere shortening rate; that ara bird has a telomere shortening rate of 50 bp/y...much less than the albatros; like humans, humans have a shortening rate of 30-70bp/y (50 avg.); like aras living 110, humans live 120). It means that albatrois bird are facing strong ROS...and despite their telomere lengtening they lose too much Too Quick; like mouse; that lose 5000 bp/'s not their length of telomeres it'S how fast you lose it/the rate of chromosomal end-termini telomeric DNA repeats erosion. It'S why humans live this long, because they protect/coast it/glide it; and make sure to have a Very low telomere shortening rate - that requires keeping low ROS - all life.

Like clams or greenland sharks that live 400 years. Clams heart beat -> 5-10 beats per minute. Greenland shark heartbeat is nearly 1 beat per minute (almost dead), their gigantic heart 'pumps' in a powerful 'pump' - once, per minute; humans we have small heart; that beat fast at 60bpm;;it's why we live to 122...and not 500.

IT's a problem; how do we get around our inherent fast-metabolism limit(s)....IF metabolism is related to longevity (it is not 1:1 perfect..but in mammals...yes,, tehre is a trend..t.he slower the heart rate, the longer the lifespan; heart rate is deterministic of body metabolistic rate, this has been measure from a mouse (5000 beats per minute/lives 2-3 years) to a greenland shark (1 beat per minute - 500 years). If we beat at a constant 60 beats/min...and live 120 years...that means a multiplier of 2x. And what is strange is that people who had lower heart rate (bradycardia) or faster heart rate (tachycardia) lived about the same lifespan - 90 years or so; so, I mean you must maintain 60 for Large majority of your life...but you acn have periods in your life where you are 50....or 90 bpm...of couse at 90 are aging in acceleration - if you keep at that fast heart rate for Decades. This is akin to people with high blood pressure and thus, fast heart rate. In centenarians humans they found Higher heart rate; which meant Preservation of the brain functions (brain function = blood hungry/oxygen hungry/glucose hungry/cholesterol hungry for membrane fluidity); that needs a strong heart taht pumps; a weak slow heart can make a slow mind/face mental retardation in the long run; it's why they saw that the centenarians with the sharpest mind made 'mild tachycardia/fast heart rate increase'; I mean they are older so the heart is 'compensating' working harder to get enough blood to the brain for mental function. It seems that in humans preservation of mental funcion is Crucial to longevity and taht means having 'enough heart rate'...not too slow - Nor - too fast (age faster/faster metabolism); but not an ultra-torpor 'dead' slowmo metabolism neither (bradycardia); like a clam or a greenland shark which have, basically, no metabolism. It's impossible in humans.

That is what worries me; a heart can beat for 500 yaers in a clam and a groenlan shark...but can it do the same in a human; I mean if we revert the age of the heart (epigenetically and damages); they it could be forever so long as we do the 'loop d loop' on and on...rejuvenating/reversing age.

But I'm not sure it is so easy/possible; it's why I worry the heart may be the biggest obstacle organ in longevity (along with the pruning brain); it must be a new 'young pump'; it can't be damaged and continue pumping will stop at some point (heart arrest). And we know in centenarians they accumulate Transthyrethin 'amyloid' like brown pigment in the ultraold heart. tAths' another problem that we have to make bacterial-sourced enzymes that break down transthyretin, lipofuscin, glucosepane and whatnot...after that we have to Lengthen the telomeres of cardia cells- only then, can we continue 'beating at 60 bpm' for whatever number of those hearts in those animals that live half-a-millenia. Studies said that a mouse's heart = a human's hear = a clam/greenland shark's heart....???? How so?

5000 beats per minute in mouse in 2 years = 100% of 'a heart's life 'in total beats'
60 beats per minute in human in 120 years = 100% of 'a heart's life 'in total beats'
1 beat per minute in clam/shark in 500 years = 100% of 'a heart's life 'in total beats'.

So what this means, is our hear is no better than a mouse's heart..and a greeland sharks heart is no better than ours; what it preservation of resources/spending of resources; a mouse spends 100% of its heart in 2 years (by beat 500-1000x faster/using/'spending it real quick'), a human spends 100% of his/her heart's capacity in 120 years; and clam/shark 100% in 500 years; and, we clearly see, that in verterbrate mammals/aviary animals, their heart rate dictate how long they live (avg. and MLSP). Still metabolism can be uncoupled from heart rate; but, the trend is pretty solid (in mammals); humans overcome their fast metabolism by pristine antioxidation systems; if we didn't we would never live 120; but only 20-25. This means our fast life/metabolism is not 'meant' to make 120 yaers old; and espeically not 500 years old; like clam/shark; when they have nearly-dead metabolism. It's still a riddle; but hopefully damage reversal/rejuvenation is able to be enough/enough of a rejuvenation taht we would revert damage; and can repeat ad vitam eternam - so we indeed Circumvent the problem of 'limited lifespan of a heart'.

Just a 2 cents.

Posted by: CANanonymity at July 18th, 2020 1:11 AM

PS: Sorry for the very lenghty message (was getting ahead of myself). TL DR: it's complicated but heart rate/lifespan metabolism are related, and why we live how long we live; same in birds.

Posted by: CANanonymity at July 18th, 2020 1:19 AM

PPS: The solution to a failing heart in longevity; is a mechanical/synthetic robo 'pump' heart; but even that is still iffy...and nano tech/electro-mechanical hears still don't last forever; they fail after a few years; but making a new heart in lab using 3D printing cell scaffolds; by making a 'real heart' could be the solution; but we would have to do this for every organ too (since they all age); and the brain...we have problem; how do we 'transfer' our memories/neuron patterns in the new-made in lab organ brain...we're not there yet (maybe not in our lifetime); it's why it is faster/better to focus on repairing damages/reverseing them and reversing aging 'at large/in whole body'...'replacing organs' may not end up suitable enough; only a 'helper' should one of our organs fail (excep the brain, where it is very peculiar with our memories/'soul'/identity in our neurons)). We will ahve to find a way to 'transcribe' 'neuron data/DNA' in new neurons - to make the memories/recollections/identiy be 'copy/pasted' in a new brain's neurons. Because no one will want to be 'cloned' into a new person - but without their memories/identity; it would mean 'erasure' of the person' former mind/identity/memories. Which means, basically, death sentence, like pulilng the plug from a cyborg robot...(just go see the film I, Robot....the scene where they say :'' I will unplug you...and then you don't exist anymore/in the will be a 'new clone robot' but your former 'identity' erased/wiped out; just like pressing the delete key''.

Posted by: CANanonymity at July 18th, 2020 1:46 AM

Thanks CANanon for that excellent analysis of various issues. I think we should distinguish between extending life by another 10-50 years from what would be needed to live another 100+ years. Clearly the latter would need to account for "debris" of various sorts, as noted for the case of the heart. However, periodic senolytic and plasma treatments alone, might be enough to add another 10-50 years - we'll see!

In general, I see selection/evolution as a very clumsy/stupid process compared to what humans can accomplish with direct intervention. This makes me skeptical of the skeptics who emphasize various limitations that evolution was faced with (such as lifetime heart beats). Yes, it's valuable to understand those limitations, but the point then is to figure out ways to overcome them, not to live within those bounds. (Something like the difference between dealing with COVID-19 via herd immunity vs. active development of clever vaccines and treatments.) In particular, the past emphasis on calorie restriction/fasting, was probably misleading since we are clever enough to extend life without starving ourselves, and should get on with that. :)

Posted by: dtkamp at July 18th, 2020 8:22 AM

Somewhat random, just wanted to say I see a tie in between flight and hypoxic environments. It has been my observation that most long lived species live in hypoxic environments.

Posted by: JohnD at July 20th, 2020 1:56 PM
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