stem cells in their environment
What is ageing?
27 March 2015
By Christine Weber
From a molecular perspective, ageing is a progressive decline in a tissue's ability to maintain homeostasis and regenerate itself. It is a process that uniformly affects all cells in the body; and, as whole tissues begin to degenerate, organs lose their efficiency and deteriorate, or are afflicted by diseases – with all the known physical, psychological and social consequences for the affected individual.
Some tissues or cell types might keep their regenerative capacity longer than others, but they all eventually age and degenerate. And as the cells within the organism lose their integrity, the entire human being is destined to suffer the consequences.
The current science perspective is that ageing is caused by degenerative changes in tissue stem cells, their niches and systemic factors that regulate stem cell activity. When stem cells age, many processes can influence or undermine their function. Because tissue stem cells persist for a lifetime and maintain a specific tissue, degeneration can have dire consequences. To function properly they need to adhere to an exact balance between active and inactive (senescent) phases, and whatever DNA damage they accumulate during their long life-span will be passed on to all daughter generations.
Common ageing phenotypes within the stem cell are shown in red, in the niche in pink, and the strategies by which to target and hopefully reverse these mechanisms in purple.Debbie Maizels / Nature Publishing Group
What does an old stem cell do differently?
Stem cells in tissues have been found to display many phenotypic changes with increasing age. These can include:
Such changes in stem cell functions can be caused by the accumulation of toxic metabolites. As reactive oxygen species (ROS) build up inside a cell, they can profoundly alter a cell's function and fate control. One theory for this is that inside a cell, mitochondria integrity regresses over time, which increases ROS production. Moreover, DNA damage is accumulated over time within the cell's genome as telomeres, which otherwise protect the chromosomes and prevent DNA loss, are becoming shorter. However, the real extent of DNA damage in an ageing cell is difficult to judge. Some genomic alterations might just represent ageing-related strategies to deal with an altered physiological situation. In fact, there are many repair mechanisms that can potentially fix DNA damage. However, several studies have shown that the efficiency of these mechanisms declines with age. Interestingly, naturally occurring mutations in important repair pathways can result in diseases which mimic the process of ageing (progeroid syndromes).
Can (and should) we reverse the ageing process?
So if ageing just represents an overall exhaustion of the cells and their capabilities, is there anything we can do about it?
The fact is that, for many of the "symptoms" of ageing, there are – at least in theory – approaches that could improve or even fix each issue on a molecular basis. DNA damage pathways can be enhanced, protein degradation can be prevented, mitochondrial function can be restored, and in order to replenish the pool of healthy stem cells, cell transplantations might be possible in the near future (e.g. haematopoietic stem cells have been routinely transplanted in the clinic for decades; a more in-depth review on this subject can be found here).
Do strategies exist that would tackle all the cellular ageing-related problems at once and in a controlled manner? The previous article in this blog explored a new method, called parabiosis, that allows the reversal of some cellular symptoms of ageing. All of the "rejuvenating" factors that have so far been found with the help of this method have one thing in common: they are pushing the aged stem cell back into a more active, youthful state. Activation of stem cells indeed seems to be the most common mechanism in rejuvenation of old mice after parabiosis.
One of the factors discovered by the lab of Professor Amy Wagers, GDF11, can trigger all sorts of miraculous changes, from reducing cardiac hypertrophy to enhancing neural stem cell function with far reaching consequences including improved physical and mental activity. It's quite fascinating to see how much "youthfulness" can be restored this way.
Erasing a cell's memory
But accumulated DNA damage might still remain and limit the extent to which a cell can be rejuvenated. Another remaining question is whether stem cells have an epigenetic memory for ageing. Stem cells accumulate epigenetic changes during their lifetime in response to external stimuli (e.g. stressful situations), and studies have shown that these changes can even be passed on to their daughter cells. Some epigenetic variations have been linked specifically to ageing. The cell might down-regulate certain enzyme levels as it adjusts to a different metabolism and so on.
However, these epigenetic changes can be reversed. Pharmacological modulation already allows us to alter histone modifications and could therefore be able to erase some of the epigenetic memory. A more extreme approach is used in induced pluripotent stem cells where the entire previous "memory” of a cell is erased and the cell is reverted back to a "blank canvas” pluripotent state. Given that there's not too much hardware damage in a cell's DNA and all the necessary instructions for the building blocks are intact, it should be possible to repair everything else and reset the cell to an earlier/younger state. Would that make a cell immortal? Could we just keep erasing the age-memory and rejuvenate them every few years? How long would a cell like this last? Would we even want to amend cell functions that we have gained (or lost) over the years and are all changes that come with age necessarily bad?
Even though it is technically possible to reprogram cells in a dish, the approach might not be feasible for an entire organism. Professor Wagers' rejuvenating factor is certainly a step closer to home, and together with Professor Lee Rubin she is currently working on getting it into human clinical trials.