Wednesday, August 17, 2005

How and why do we age?

` (I'm finally posting this entry, which is way back from 17, July 2005; one month is about the longest I can bear to sit on my poor, neglected drafts! Especially when they look at me all pitifully and start whimpering like that...)

` I came across a number of happy EMBO reports. I don't know if these eventually become inaccessible over time like News@Nature stories, so instead of linking to them, I'll just write a little bit about them. Why? Because I think some people might be interested.

` There are a bunch are about what causes aging - or 'ageing', as this is a British publication.

` This one is by Thomas B. L. Kirkwood, called Time of Our Lives.

` Yes, what exactly does cause us to only live to a certain age, barring illnesses and accidents? First, he tackles the question of whether we have a pre-set 'clock' that tells us when we're supposed to die. Long story short, as there is no real evidence for this, the conclusion is "No," - so, what else could it be?

` Is it genes?

` Well, take identical human twins. They don't always age at the same rate. (This may have something to do with the way their gene expression differs from one another more and more throughout life.) And when you consider experiments with the nematode C. elegans; even when they live in the exact same environment, many nematodes with the same genes for aging can turn out widely different in the aging and lifespan departments.

` So, not exactly.

` Over two thousand years ago, Aristotle once promoted the idea that having sex hurts one's lifespan. This may be true for Drosophila (fruit flies), but not humans.
That's a good thing, because it means that the sex-suppressing beliefs of people like Kellogg and Graham (famous for inventing the sex-suppressing breakfast cereal and crackers) were wrong. (In fact, I think having sex is known to make people healthier!) Fertility, however, may have something to do with it: Women who have less children live longer.

` And then we have the question of how much the wear and tear of cells affects lifespan. Considering that germ lines of all species alive today are billions of years old, and considering that some organisms, such as the primitive animal Hydra, do not age at all, it can't be as simple as that.
` It is possible that organisms age because, after they're old enough to have reproduced sufficiently, they no longer need to survive to pass on their genes. Germ lines, on the other hand, do, because they are the cells that go on to become offspring. Because of the way it reproduces, Hydra would therefore not age because there is no difference between its body cells and its germ cells.

` A lot of aging has to do with mutation and damage in the DNA of body cells. Some of this has to do with the caps, called telomeres (TEE-lo-meers), found on the ends of the chromosomes. In germ cells and some adult stem cells, there is enough of a type of enzyme, telomerase, to replenish the telomeres as the cells replicate. Most body cells don't have this, and as the telomeres degrade over time, so do the quality of the cells. Stress, especially from oxidation, will greatly speed up telomere erosion.
` Also, since mitochondria don't have much to defend their DNA (they have different DNA than do the rest of the cell), mutations are bound to accumulate there. Tisuues which have this problem are not as well-able to regenerate themselves.
` In fact, I personally remember a Nature article in which mice that were bred with no defenses against mitochindrial DNA mutations aged about a year in each month compared to other mice. (In other words, this was an artificially-induced mouse-progeria!)

` A large problem also has to do with problems the cells have with clearing out used proteins and bringing in new ones. This kind of cellular damage results in all kinds of disorders, from cataracts to Parkinson's disease.
` As more cells become damaged, the more apparent problems become. So definitely, damage over time is a big problem. And it's not just damage, but the declining ability for aging cells to repair it.

` On top of this all, for the past seven decades, people have known that not feeding lab rodents as much as they are supposed to eat will extend their lifespan. The same is true of fruit flies, nematodes, spiders, water fleas, and fish. In fact, it even seems to be true of yeast! It may also be true of primates (like us!), although apparently, it is not certain.
` (Here I am reminded of a TV show I once saw - microscopic slides of biopsied muscle tissue from monkeys given low calorie diets were compared with ones given 'normal' diets:
Twenty-year-old monkeys on the restricted diets had the same amount of tissue damage as five-year-old monkeys on standard diets.)
` Now, when you 'underfeed' rodents, their bodies are better able to maintain and repair themselves, and at the same time, lose their ability to reproduce. This would make sense: When you don't have enough to eat, you will have trouble supporting offspring - so what you do is preserve your own body as best you can so that you'll survive to reproduce when it's over.
` Also, as everybody knows, what type of nutrition you get definitely affects your lifespan, so in many ways, food is known to affect how long you live.

` Evidently, aging is a very complicated process - so much so that different theories of aging have, in the past, been mistakenly thought to be competing models. Speaking of which, here is another such theory:

` Programmed ageing: the theory of maximum metabolic scope, by Roland Prinzinger (Head and Chair of Metabolic Physiology at the Jonathan-Wolfgang Goethe University, Frankfurt).

` He asks; does anything really have to age? For example, an inanimate object will wear out, even with maintenance, but that is because it is unable to constantly replenish its own constituents. On the other hand, humans can replace 90% of their tissue completely in seven years. It would therefore seem possible to keep an organism alive as long as it could renew and repair itself without problems.
` The reason why organisms don't live forever is because nature needs to replace the life forms it has with new ones in order to test the effectiveness of their differing genetic variations. Give an organism immortality and it fails to make room for other ones - including its offspring.
` Therefore, Prinzinger writes; "...death is the basic precondition for the frictionless and rapid development of new species that can successfully adapt to changing environmental conditions. This is an evolutionary principle."

` So why do we age? Why do we lose the ability to repair ourselves? Perhaps the fact that this happens is actually genetically determined along with a lot of other things.
` I guess that isn't completely out of the question.

` Now, this theory both explains why many organisms slowly lose functioning over time, as well as why some organisms suddenly die when they are in perfect health. For example, many plant species will die just after flowering, and there are thousands of animal species which will keel over just after reproducing or even copulating successfully.
` A dramatic instance of this occurs in the spectacular Argiope spiders: After mating, the male's heart suddenly stops and the female can then eat him at her leisure. I am supposing here, that if the male is never given the chance to mate and is protected from freezing temperatures, he will live much longer.
` (This reminds me of what happens to people's backyards: Back home in Ohio, we erected a chain-link fence in order to keep a certain criminal neighbor from constantly meddling in our yard. The grass that sprouted up tall inside of the fence where it couldn't be cut would go to seed in the late summer and die, while the mown grass, still unable to reproduce, often survived the winter.)

` When you think about it, a lot of mutations affect the aging process: There are mutant fruit flies and rodents which produce long-lived offspring. And of course, we are well aware of mutations that cause rapid aging, such as Werner's syndrome.
` Really, our very cells are programmed to die - apoptosis is a process by where a cell will simply kill itself (a phenomenon of such importance that I've noticed it has its own unique section in Nature publications). But, like the death of entire multicellular organisms, cells need to die in order to be make room for and not hinder newer growth. Without apoptosis, we would be mishapen to the point where we could not survive the embryonic stage.
` (Of course, as not all cells die in your own lifespan, what keeps them alive? Recent case in point: it's just been discovered that cells in the optical cortex are not replaced. They must not be programmed to die!)

` So, yes, the cells of organisms are definitely able to die on cue, and there is much evidence that at least some enitre multicellular organisms can suffer some kind of fatal damage at a specific time in their lives. This element of 'programming' seems to be strong in many, if not all life on earth.
` But how far does it go?

` Consider that every species has a 'typical' lifespan-range which cannot seem to be surpassed (unless perhaps there is a mutation!). While different species may have entirely different lifespans - a shrew only lives about a year and an elephant may live past sixty - a shrew could not hope to live as long as an elephant. (Of course, a lot of this probably has to do with the stark differences in heart rate and metabolism.)
` As for human beings, eighty seems to be about as old as you can get... maybe over a hundred if you're lucky. It doesn't matter what the average lifespan of your population is - in the Bible, it is mentioned that people could live to be eighty (while only half the population survived past eighteen), and in many primitive populations today, eighty up to a hundred seems to be about as old as you can get.
` With modern civilization came improved nutrition and health care, but has that extended the potential, biological lifespan of humans? No. But now it is much more likely that you will live to your upper limit.

` It also seems to be true that, with any genetic population, in nearly any culture, at any time, women tend to live longer than men. For example, in 2002, the average ages for Germans were 82.0 years for women and 75.5 years for men. In 1881, women lived only 38.5 years and men lived onl7 35.6 - the number is affected by the fact that more of them died as tiny infants, as many were more often killed by various things that were harder to control back then, though a lot of people still managed a good eighty or more years in life.
` As this is different from one's potential, or physiological, lifespan, the average lifespan of a population is called the ecological lifespan. The ecological lifespan is controlled more by environmental conditions than anything, so evidently, it tells us how well individuals hold up against the odds of local conditions.
` And since the mean age of women in any population seems to be above a man's ecological lifespan, no matter what the conditions are, it would seem that women have an easier time of surviving just because they're women. In fact, differences in the lifespan between the sexes is also normal for other species. So, there's gotta be something that controls it.

` Next in his paper comes some delicious charts showing how potential lifespan, as well as the different stages of development, are strongly correlated with body mass in all organisms. For example, in most animals, the larger you are, the longer you'll live, according to this equation which I can't get the html to display properly.

` This is as far as I got on July 17th. Now I'm finishing up:

` The equation basically shows that the chronological lifespan (A) consistently varies with the fourth root of body mass (M). The coefficient a may be different between taxa, but the exponent only varies between 0.23 and 0.27. Not only is this true for the entire lives of animals, but even for the different stages: The durations of embryology, ontogeny, and the adult phase in various types of birds are correlated with mass, which he shows a chart of.

` Also, things which expend a lot of energy tend not to live that long. He gives lots of examples:

~ If you raise the temperature in the medium of various single-celled organisms so that their metabolisms double, their lifespans will end (they divide) in only half the time.

~ Animals that are 'frugal' with their energy - such as crocodiles and turtles, live a particularly long time.

~ Parrots and birds of prey that are kept in cages, unable to 'experience life', will live longer than they would in the wild.

~ Invertebrate animals which are active, like octopuses, live only about 4-6 years, while unmoving shellfish of the same body mass can easily go on for 20-40 years!

~ Animals that hibernate or become lethargic live much longer than those who don't slow down. White-toothed shrews, for instance, are capable of lethargy and can live 4 to 6 years. The similar-sized red-toothed shrews are always active but only live 2 or 3 years.

~ Mice that are given a 'hunger diet' may live twice as long as mice which always get enough to eat.

~ A male rat that's had its testicles removed can live anywhere from 5.3 to 8.1 years. Castrated humans may live fourteen years more than they would otherwise. (Veterinarians all say that doing the same to dogs and cats causes them to live about 2 more years.) This makes sense because their energy turnover is not nearly as much as it otherwise would be.

~ Males live 10% longer than females, and they consume about that much more energy.

~ When one's thyroid is overactive and their metabolism goes up, they will not as long as others, though this isn't true for underactive thyroid.

~ Animals that use up a lot of energy - like hummingbirds and shrews - don't live too long, while mussels and turtles and things that are very sparing in energy consumption may live an insane amount of time.

~ Rodents, humans, and other animals will live unusually long when they are deprived of energy intake.

~ Caloric deprivation extends the lifespan of species such as Saccharomyces, Caenorhabditis and Drosophilia.

~ People who get lots of sleep and are sluggish in behavior live longer than people who go through hard physical labor.

` So I guess, if you lived a sheltered, caged, boring, sluggish, starving and non-testosterone-filled life, you may be miserable, but at least you'll live long enough to see all your friends die.
` ...Yeah. Anyway, this is basically a rule in nature, which of course has exceptions, but it truly is a general pattern.

` Metabolism is just about identical for all life forms that breathe and live in oxygen, and this is why it would seem a likely candidate as a 'timer' for one's lifespan. Therefore, perhaps it measures time in terms of energy consumption.
` Practically all life uses mitochondria to take oxygen, combine it with molecules from food, to create ATP - which, so you know, is a molecule that stores and releases energy for work.
` Mitochondria themselves, as they have their own DNA and reproduce independently from the rest of our cells, probably used to be bacteria-like organisms that took up residence in our single-celled ancestors. They became symbiotic, used by the host to produce energy - a very useful thing indeed! - and can be seen in single-celled organisms, and us multicellular animals, as well as fungi and plants.
` They're also practically the same no matter what the 'host' organism. And in all cases, they have a limited functionality and lifespan. Apparently, mitochondria can only a certain amount of energy before they die - which in turn kills you.

` That makes sense. Your mitochondria can only metabolize so much before they stop functioning. So, if you are more sedentary and don't have a lot of stress in your life, they don't work as hard, and you live longer. The more you work them, the more they wear out. And that's nearly universal.
` Pretty simple, on a basic level. I wonder how many mutations mitochondria can get that will keep them working longer (the opposite of the 'progeria mice' I mentioned)? Hm.

` Anyway, this Prinzinger chap may be onto something, though - as it is with new proposals - there will probably be many modifications and additions if it is to turn out properly.
` Certainly, I would say that his theory is probably very important in any case.

` And, since this is such a horrendously long post, I'm going to stop right there, even though I could go on. I hope anyone that was looking for this type of information or at least thinks it's neat found this entry to be useful.


jon said...

one time i was at this creek and all these fishes were swimming up to lay there eggs and die, while some fish were just swimmin around in the sea, i didn't see em but i know they were there just being big and stuff. the real question is what makes these fish decide to go up stream and die or swim around and be big

S E E Quine said...

` This is true. They COULD live longer - it's not like they have to swim upriver. Perhaps it depends on the way their lives go, which affects gene expression.
` Even more weirdly, some male salmon will stay in the river they were born in and not grow at all. Then, when the other salmon come up the river to spawn, they will fertilize as many eggs as they can without the big male salmon seeing them.
` I don't know what determines whether or not they do that, either - but it sure beats absorbing your internal organs and dying!

jon said...

hahah, thats funny. those males sure are sneaky

S E E Quine said...

` Hey, you know what's really weird? Orangutans do the same sort of thing: Some of the males don't grow very big and fail to develop those big pad-things on the sides of their heads.
` The larger, dominant males think they're only 'kids', so the small males are free to try their luck with females right under his nose!
` It seems strange to me that apes can stunt their outer development as a mating strategy in about the same way as some fish - which do strange things like this all the time.
` I guess it's because orangutan males tend to be alone most of the time, so it's hard to keep track of their ages. I don't know...