|Abstract:||All things are ageing. – All things? Not everything! Although ageing is quite widespread, it is not a universal phenomenon. Ageing is actually an incredible plastic process which can be speeded up, slowed down, totally stopped or even reversed. Understanding what determines to age or not to age, the pace of ageing, and how modify its rate or even reverse it, would unlock the capacity to fight all the age-related reduction of functions and the negative changes which afflicts us as we get old.|
Ageing is one of the most ancient mysteries and the chief biomedical problem of the post-genomic era. It is the progressive decline in all physiological functions, resulting ultimately in the thermodynamic equilibrium, i.e. death. It is seen in numerous (although not all) species and its mechanism appears to be highly conserved as it was invented early in evolution.
Why we age? Evolution works via replication (reproduction) under variations (mutations) and selection (environment). Natural selection for maintaining a functional body after reproduction is not great. In contrast, there is even multitude of forces for the elimination of parent individuals which are more experienced and compete for resources with their own progenies. Even a small fitness reduction of the older individuals increases their probability to die. Further, in competition with non-ageing species, ageing species would have a greater gene pool (higher variations) and out-compete the non-ageing species, because they can adapt better to changes in the environment. In such ageing speeds up evolution by increasing generational turnover in most environments where it is favourable. Whether ageing is mediated actively or passively is a philosophic question.
The exact molecular mechanism and the root cause of ageing is unknown.
Fact is that each species has a specific lifespan which best fits its biological niche. Some species age very rapidly and have a high generational turnover with a lifespan as short as a day (e.g. mayfly). Some are relatively long-lived (like primates including our own species), while several other organisms do not appear to age at all and have no functional decline with increasing age (such as turtle and rockfish) or where even classified as immortal (red sea urchin and hydra). Impressively, there are plant individuals which were shown to live over tens of thousands of years. Therefore, nature generated a great variety of ageing phenotypes.
The above examples illustrate that ageing is not due to fundamental problem in metabolism, but rather is determined by the individual genomes which are shaped by their specific environments. Actually also the same genome can give rise to dramatically differences in lifespan with for instance social insects like ants and bees, where the short-lived workers are hugely outlived by their queens. In honeybees the decision to become a short-lived worker or a long-lived queen is due to the feeding of a few selected larvae with royal jelly (a special diet), which reprograms the genome to slow ageing.
Thus, there are not just interspecies differences in lifespan, but also great variations within a species. Feeding an animal less than it would consume normally, called dietary restriction (or caloric restriction) is a non-genetic intervention shown to extend lifespan of a multitude of ageing species. Feeding half as much as normal makes rodents live twice as long. Eating less also prolonged the lifespan in non-human primates and the exceptional longevity and health of Japanese Okinawans (longest lived and most disease-free population on the whole earth) appears to be attributed to their dietary restriction-like lifestyle. It seems that restricted animals activate a specific program to slow down ageing in times of famine in order to be able to survive and to reproduce later on.
Life comes with instructions. All information of an organism is encoded in its genome consisting of genes and regulatory elements as well as structural regions. Ageing appears to be controlled greatly by genes and even environmental influences are mediated by specific genes. The lifespan extending effect of dietary restriction can be mimicked and/or cancelled out by mutating certain genes.
The genetic basis of ageing is very intriguing. Some mutations of defined genes cause premature ageing (called progeria), where kids suffer rapid ageing and die on age-related diseases (sometimes even before becoming a teenager). In contrast, mutations of other single genes extended the lifespan of animals up to ten-fold. Mutating just two genes stopped ageing all together. Finally, manipulation of only one defined gene can make old organisms young again.
There are genes which mediate ageing (the bad guys; gerontogenes) and other genes which antagonize ageing (the heroes in our genome; ageing suppressors). Consequently, suppressing the bad ones and activating the good guys counteracts ageing and has the potential to restore youthfulness.
Actually, when we are young everything is better, our body is highly functional and can defend against all kind of threats, wounds are closing rapidly and our cognitive capacity is great. As we reach maturity we get the highest peak of most of our functionalities. However, normally in an ageing organism right after the completion of development the ageing process starts. Developmental processes are tightly regulated and even so ageing. Ageing gene expression changes seem actually to originate from development. Some rare-cases of human individuals, which are stuck in development, are not maturating completely and do not begin to age. This represents right the opposite of the progeroid kids in which the ageing process is premature activated.
However, there is hope even for the already aged. Ageing is in fact reversible. Accumulating evidence showed that age-related changes, including in mammals, can be reversed. There is a real rejuvenation process, sleeping in our genome. It is activated as we pass our cells to the next generation. Therefore, our children, regardless of which age we get them, have a restored lifespan. Ageing was truly reset. It is a remarkable phenomenon, but most do not realize it. If it would not, each generation would be born older and older, but obviously they are not. It is possible to re-awake it also in our body cells. It was done in model organisms; it can also be done in humans. We just have to identify the right genes and understand the semantics of the sequences in our genome.
Understanding the very nature of ageing will enable us to manipulate ageing effectively for the health and well-being of humans. Unlocking the capacity to rejuvenate will be the most potent way. Lifespan extension by dietary restriction is the most powerful non-genetic intervention acting on the ageing process and may provide us with the hint on the cause of ageing.
Why we age? This is a fundamental question of crucial importance as it deals with the cause of ageing and when answered correctly would subsequently make it possibly to find interventions with unpredictable health benefit for mankind. Recent data showed that age-related changes can be reversed by simply activating a single transcription factor [Unal et al., 2011]. Therefore, ageing is not simple due to the irreversible accumulation of age-related damage and the reversal of ageing is not any more theoretical impossible. It might be argued from an evolutionary perspective that ageing is simple due to the lack of natural selection forces after reproduction. Changes which are beneficial early in life may become detrimental later in adulthood (antagonistic pleiotropy). There is even evidence for programmed ageing operating on the level of group selection, hence altruism [Fabrizio et al., 2004]. Strikingly, the involved pathways include nutrient sensing as well as growth regulation and are evolutionary well conserved. In light of this view, ageing is a process speeding up evolution by ensuring generational turnover and gives a great advantage to a population in a natural environment which changes. We age because the environment is changing. Nothing in evolution makes sense except in the light of population genetics. Dietary restriction (DR) extends lifespan in multiple species. It might be an evolutionary conserved response to famine, slowing down ageing and reproduction in order to be able to reproduce when resources are again plentiful. The lifespan-prolonging effect of DR can be abrogated by genetic interventions of DR-essential genes. Whatever the mechanisms of DR is, it needs to be deciphered as it the most powerful non-genetic intervention to retard ageing and as it appears to affect the basic ageing process itself, it might give us clues to the actual cause of ageing.
Reversed mortality rates of Drosophila melanogaster that have been switched to DR are a consequence of a reversal of the damage [Mair et al., 2003]. The ability of repair and replacement systems to reverse the damage accumulated since birth so rapidly argue that organisms normally maintain a sub-optimal level of protection [Longo et al., 2005]. Yeast undergoes an age- and pH-dependent death with features of mammalian apoptosis. After 90-99% of population dies, a small mutant sub-population uses nutrient released by dead cells to grow. Adaptive regrowth is inversely correlated with protection against superoxide toxicity and lifespan and is associated with elevated age-dependent release of nutrients and increased mutation frequency. Ageing together with relatively high mutation frequency can result in a major advantage in adaptation to changing environments. Yeast organisms undergo an altruistic and premature ageing and death program, mediated in part by superoxide [Fabrizio et al., 2004]. Whatever the cause of ageing is, it needs to be deciphered.
Unal E, Kinde B, Amon A (2011) Gametogenesis eliminates age-induced cellular damage and resets life span in yeast. Science 332: 1554-7.
Fabrizio, P., Battistella, L., Vardavas, R., Gattazzo, C., Liou, L.L., Diaspro, A., Dossen, J.W., Gralla, E.B., and Longo, V.D. (2004). Superoxide is a mediator of an altruistic ageing program in Saccharomyces cerevisiae. The Journal of cell biology 166, 1055-1067.
Mair, William, Goymer, Patrick, Pletcher, Scott D, Partridge, Linda (2003) Demography of dietary restriction and death in Drosophila. Science 301: 1731-3.
Longo, V.D., Mitteldorf, J., and Skulachev, V.P. (2005). Programmed and altruistic ageing. Nature reviews Genetics 6, 866-872.