This is a chaotic collection of links, thoughts, ideas about ageing and represents the way the author sees it.
It is in no way scientifically sound and is intended to be a "living document" and improved over time.
... THIS PAGE IS HEAVILY UNDER CONSTRUCTION ...
To understand what the microscopic (molecular) reasons are as to why different species age at different rates one first has to normalize their (maximum) lifespans in respect to the macroscopic parameters temperature and mass specific energy turnaround.
As a first approximation one gets the result that the maximum lifespan is inversely proportional to the mass specific energy consumption (neglecting temperature for the time being). Or put it differently, the product of the maximum lifespan and the mass specific energy expenditure is constant. This is the so called Rate Of Living Theory of Ageing. It says that 1 gram of biological matter can burn roughly 500 kcal before it is exhausted. For the whole organism one can therefore calculate a so called life potential which is the number of calories it can burn until it inevitably dies.
Ageing therefore is a general property of biological matter and is not due to the specific construction of a certain species (e.g. genes), at least as a crude approximation.
A better understanding of this theory has been given by West et al.,
see e.g. Biological Scaling and Physiological Time and the lecture 1 2 3 4 5 6 7 8
Their claim is that
The quarter power dependence of the maximum lifespan is due to a geometric effect. Qualitatively it can be understood quite easily, though it is a bit bit difficult to derive mathematically.
It has to do with the fact, that energy is supplied via so called branching networks, the blood circulary system being one example. Naively one would expect that if one doubles the mass of an organism the energy supply capacity (e.g. the mass of the capilaries) would also double for the individual cell to receive the same amount of nutrients and energy. Surprisingly this is not the case, as these branching networks are fractal in nature and their mass scales as m^0.75. This means that the bigger an animal is, the less energy an individual cell can maximally receive and the higher the upper limit for the maximum lifespan is. (Whales being a suggestive example). The maximally possible energy expenditure therefore scales as m^0.75.
To test this hyothesis I have ploted data, taken from AnAge database which is a great source of ageing related data.
If the rate of living theory where exactly fulfilled, L0 would be the same for all species. This is not the case, still the rate of living theory works remarkably well and in my opinion can well serve as a paradigm for further investigations (i.e. trying to understand why it is approximately fulfilled so well and why deviations occur for certain species). Outstanding exceptions to the theory are for example birds and bats who live exceptionally long.
To further investigate the microscopic differences of ageing between different species one can define
L0 = M*LR.L.
with L0 see above, LR.L. the rate of living constant and M a factor that I call "maintenance factor" which describes the deviations from the rate of living theory. Birds and bats for example would have a maintenance factor larger than 1 as they live longer than average.
The following plot shows maintenance factors for different species (data from AnAge) which shows that there clearly are molecular differences between different phyla that contribute to a different rate of ageing:
... TODO insert plot ...
Interesting in the context of the rate of living theory is a study done with birds: Tropical Birds Have Slow Pace Of Life Compared To Northern Species, Study Finds
The answer to the question what the reason for these microscopic differences could be will be persued under "microscopic".
Mortality curves (i.e. plots of mortality vs. time) show a universal behaviour which is the so called Gompertz law and which is a special form of a logistic probability distribution. These distributions are based on reliability theory, i.e. the body has a redundancy in its subsystems that fail one after another as time passes leading to a system's failure once a critical treshold is reached. (Interestingly failure rates of light bulbs also show a logistic behaviour).
Why we fall apart
The convergence of the death rates reflects the fact, that there is a (universal) maximum lifespan for a given species. The different curves for different populations correspond to different mean life spans ("rectanglification of the mortality curve").
- A slow down in ageing should manifest itself in a right-shift of the mortality curve, i.e. an increased maximum lifespan. Interventions that yield this are the real anti-ageing interventions.
- An increase in the mean lifespan, leaving the maximum lifespan unchanged, just means a decrease in the number of premature deaths, i.e. a less "suboptimal" ageing.
Ageing is a general phenomenon and not restricted to biological systems and can be described as loss of information of a system with time.
The pacemakers of ageing in biological systems therefore must be structures with lifetimes of the order of the lifetime of the species that serve as the backup structures for the information. Candidates are DNA (+ methylation patterns) and mtDNA. RNA cannot serve as backup structures as due to the central dogma of biology information flows from DNA to RNA only. Furthermore unwanted stable structures, that gradually build up during lifetime and "seed misinformation" and hinder processes also have to be considered (AGEs and other kind of junk). These stable structures therefore can be seen as "ageing clocks", that is if one looks at them one should be able to determine its biological age. They therefore could serve as biomarkers for ageing.
One of the questions in search for a microscopic theory of ageing is: Is there one key effect or are there a small number of key effects that are the pacemakers of ageing, or is ageing a superposition of many effects. If the latter is the case, I think it will be very difficult to fundamentally counteract ageing. I suggest a theory for this below ("Theory of quasi synchronous ageing").
The most prominent theory at the moment in the scientific community alluding to the former situation, i.e. there being a small number of "bottlenecks" or one single "bottleneck", preventing a considerably longer lifespan, seem to be the free radical theory of ageing. Closely related to it is the mitochondrial theory of ageing.
Free Radical Theory of Ageing:
The Free Radical Theory of Ageing Matures
Oxidative Stress and Ageing: Beyond correlation
Induced overexpression of mitochondrial Mn-superoxide dismutase extends the life span of adult Drosophila melanogaster - "Life span was increased in proportion to the increase in enzyme. Simultaneous overexpression of catalase with MnSOD had no added benefit...Cu/ZnSOD overexpression also increases mean and maximum life span. For both MnSOD and Cu/ZnSOD lines, increased life span was not associated with decreased metabolic activity, as measured by O2 consumption."
Relationship between mitochondrial superoxide and hydrogen peroxide production and longevity of mammalian species
Higher Respiratory Activity Decreases Mitochondrial Reactive Oxygen Release and Increases Life Span in Saccharomyces cerevisiae
Antioxidants and aging
Mitochondria Theory of Ageing:
Ageing is the ongoing loss of information and without vehemently counteracting this process, biological system would decay very quickly due to the relative instability of its chemical constituents (mainly proteins) and due to environmental influences (biological systems are open systems) - dead cells desintegrate very quickly as is quite obvious. To maintain a biological system, i.e. steadily repair it's DNA, defend attacks of viruses, bacteria etc., energy is required. DNA repair for example is a extraordinarily sophisticated process, but it requires a lot of energy. The provision of energy (mainly in the form of ATP) however is a "dirty process". As a byproduct highly reactive chemicals are produced that, due to their vicinity to the mtDNA, mainly damage this genetic code. Moreover the repair of mtDNA is not as sophisticated as is the repair of nuclear DNA. As a consequence the information how to build correct proteins for the mitochondrial oxidative phosphorilisation machinery is lost over time. This leads to a decrease in the effectivity of the production of ATP in the mitochondria. When the amount of ATP reaches a critical treshold, the cell doesn't get enough ATP any more to do its maintenance work sufficently (e.g. DNA repair). This leads to an increased speed of information loss of the cell which cannot be tolerated, as it can go awry (in the worst case become cancerous) and endager the . As a built in mechanism to avoid this vicious cycle the mitochondria trigger apoptosis or necroses once this critical low energy production state of the mitochondrion is reached. The big problem is: mtDNA damage accumulates with age, so after a certain time, no cell is viable any more. This poses definitely a limit to the lifespan of a cell and therefore to the body as a whole.
Here is a collection of links to papers that deal with the problem of mtDNA damage
In this respect I highly recomment this audio: ...
A question therefore is: How would biological lifespan be affected if one could stop the degradation of mtDNA?
Red blood cells ...
As seen above, the maintenance factor of different species is nearly the same, i.e. the rate of living theory is fulfilled quite well. There are two striking exceptions: Birds and bats. Therefore nature offers us a great opportunity:
To find a clue as to why different species age at different rates one has to study the biochemistry of birds and bats !!
Birds might even be better suited than bats, because bats hybernate which has to be taken into account to calculate the average mass specific energy turnaround and which might pose practical problems.
Birds as Models of Aging in Biomedical Research
An excellent paper that gives hints as to why birds and bats might age comparatively slower is the following:
Reduced free-radical production and extreme longevity in the little brown bat Myotis lucifugus versus two non-flying mammals - "These data provide evidence in support of the free radical theory of aging... It appears that bats, like birds, have mitochondria that are able to produce the high quantities of ATP necessary for flight functions in these animals, while producing relatively low amounts of free radicals. Studies ... did not show increases in oxygen radical production proportional to the increase in tissue oxygen consumption associated with the transition from state IV to III. The reduced free radical production in state III may be in part due to the less reduced state of electron carriers of the electron transport chain. An alternative but related explanation may be that mitochondria in a cell use different mechanisms for the production of ATP during exercise... heart and brain tissue, which have high energetic demands, produce additional ATP needed through the TCA cycle pathway. Because electrons enter the electron transport chain at complex II, complex I, which is a principle generator of free radicals in the electron transport chain, does not become as reduced in this pathway. A similar result ... Mutant strains of ... fungus use an alternative pathway in the electron transport chain.This alternative pathway transfers electrons to oxygen to make water upstream from complex III, preventing the generation of reactive oxygen species at that complex. Indeed, generation of reactive oxygen species is lower...and the mutants exhibit lifespan increases of about 60%."
Moreover this suggests, that the 120 years maximum lifespan of humans is not a hard limit i.e. a physical limit, but is given by the given specific design and might be improved.
It is quite striking how little research has been done with these animals in order to find out how their unique "longevity program" works. (A pigeon has approximately the same metabolic rate and mass as a rat, still it lives about 9 times longer than the rat).
There are hints that different ROS leakage rates at Complex I of the electron transfer chain in the mitochondria are responsible for the lifespan differences.
It would be very interesting to know whether calorie restriction, which is supposed to reduce the production of ROS, could even top the extreme long lifespan of birds. So far I have found no study on this.
Endogenous oxidative stress: relationship to aging, longevity and caloric restriction - "The first bird species studied was the pigeon, an extreme case since its MLSP is nine-fold higher (35 years) than that of rats (4 years), whereas body size and basal metabolic rate are of a similar order of magnitude in both species. It was found that pigeons had less mitochondrial ROS generation than rats in all the organs studied .... It was also found that this was due in many cases to a decrease in the percentage free radical leak in the respiratory chain, i.e. pigeon mitochondria univalently produced less ROS per unit oxygen consumption than those of rats .... This could explain the paradox that birds are the only animals on earth (together with homeothermic bats) showing both high O consumption and high MLSP. It was also found that the respiratory complex responsible for the lower ROS generation of pigeon in relation to rat heart mitochondria is complex I, not complex III ...Further studies .. suggest that various complex I FeS clusters ... can be the source of ROS."
Mitochondria, Antioxidants and Aging
The rate of free radical production as a determinant of the rate of ageing: evidence from the comparative approach - "All available work agrees that, across species, the longer the life span, the lower the rate of mitochondrial oxygen radical production. This is true even in animal groups that do not conform to the rate of living theory of aging, such as birds."
Mitochondrial production of pro-oxidants and cellular senescence - "It is argued that the rate of mitochondrial O2- and H2O2 generation rather than the antioxidant level may act as a longevity determinant."
Mitochondria, reactive oxygen species and longevity: some lessons from the Barja group
Nitric oxide signaling regulates mitochondrial number and function
Mitochondrial matrix reactive oxygen species production is very sensitive to mild uncoupling - "Several studies in mammals and birds suggest that the most physiologically relevant ROS production is from complex I...ROS production in the matrix is expected to be particularly dangerous, as many important macromolecules, including mitochondrial DNA, are found here.We have shown that matrix ROS production is from complex I ...and that it is highly sensitive to a small decrease in membrane potential."
Theory of Quasi Synchronous Ageing:
This is a theory that I like to suggest (probably somebody else has already done this in the one or the other form and I don't know of it):
I claim that all the subsystems of a biological system that have to be maintained and require energy for their maintenance age at approximately the same rate. The "quasi" alludes to the fact that there are subsystems that don't require energy for maintenance or for all practical purposes don't need maintenance (generically slow/negligable ageing). Furthermore it is assumed that maintenance for a subsystem is such that its performance is sufficient for the working of the whole organism throughout life.
The reason for synchronous ageing is selective pressure. If a subsystem is maintained such that it would have a lifespan that (considerably) exceeds the lifespan of the whole organism, there would be no gain. From an evolutionary point of view it is more advantageous to spend this energy for reproduction and "to run away from tigers". As an example: One would expect that there is no subsystem in humans that has been selected to live 130 years or more, except for those that do so anyway. Therefore most of the subsystems age such that they are exhausted when humans reach their maximum lifespan.
My hope is, that this theory is wrong, because then we could expect to find a bottleneck in the ageing process, that we could fix in that we just improve one ore a few subsystems and this way could considerably prolong lifespan. Free radical damage to the mitochondrial DNA could be one such limiting factor (see above).
Mitochondrial Optimization May Be Linked to Human Longevity
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Balingen, 01.09.06 firstname.lastname@example.org (Comments are always welcome)