Scientists may have learned how to reverse human ageing. Researchers from the Salk Institute in the US and the Chinese Academy of Science discovered that the deterioration of tightly packaged bundles of DNA required for regular cell function is actually reversible – understanding how this process works may allow the development of new treatments for age-related conditions such as cancer and Alzheimer’s. The discovery was made while studying the principal causes of Werner syndrome – a genetic condition that causes accelerated ageing. The results were published in the academic journal Science.
It is thought that ageing evolved as a side effect of natural selection – the pleiotropy/trade-off theory of the evolution of ageing. Mutations that are beneficial during youth may sometimes have the opposite effect later in life. Since the force of natural selection declines with age as chances of reproducing decrease, these mutations are able to remain in the genome. For example, humans possess some genes that limit cell growth (called tumour suppressors) and some that promote it (namely proto-oncogenes).
There is a fine balance between the two, which this new research may be able to keep in-check – too much cell growth may result in cancer; too little may cause tissues to malfunction. This is important to animal survival because it balances the need for regenerative capacity whilst safeguarding from an increased chance of cancer. It has been suggested by a number of scientists that as people age, this balance skews causing a drop in stem cell function and the ability to regenerate tissue.
The team discovered that the underlying genetic mutations thought to be responsible for Werner syndrome (also called adult progeria) caused heterochromatin (densely packed DNA) to become loose and disorganised. This causes cells to age prematurely by interrupting regular cell processes. “This [disturbance] of normal DNA packaging is a key driver of ageing,” senior researcher Juan Carlos Izpisua Belmonte, from the Salk Institute. More specifically, the team discovered that the condition is caused by mutations in the WRN gene, which causes a deficiency in the WRN protein.
This protein has previously been shown to help maintain the structure and integrity of DNA, however how the mutated gene exerts its effect has been unclear until now.
By ‘knocking out’ the WRN gene from human embryonic stem cells, Weiqi Zhang from the Chinese Academy of Sciences and colleagues showed how cells were soon unable to to divide and had shorter telomeres (the protective caps at the ends of chromosome arms). In particular, the team noticed that the heterochromatin had become reorganised – the symptom identical to cells that have aged normally. The researchers then concluded that the WRN protein plays a role in the maintenance of the heterochromatin structure.
Heterochromatin is a very tightly packed structure of DNA that controls the activation of genes through the direction of various molecular parts. By removing WRN, the architecture of the cell’s heterochromatin is changed, causing the cells to age rapidly. Guanghi Liu, a director and professor of the Human Pluripotent Stem Cell Core Facility at the Chinese Academy of Science told The Positive that, “Heterochromatin degeneration is a driver for human stem cell ageing. The classic view is that ageing is caused by accumulated DNA [mutation], also called genomic instability. We found that epigenomic instability, especially the [reorganisation] of heterochromatin, is a driver of human stem cell ageing and this is a new concept in [the] ageing field.”
Promisingly, the team found that heightened expression of the HP1 gene is able to repress premature senescence in Werner syndrome and suggest it as a possible drug target for the prevention of ageing. The lab is now attempting to screen a compound that might slow down human stem cell ageing, hinting that with some luck, they might already have a good candidate. Their aim is to devise a cocktail of small molecules that may rejuvenate aged cells, with their final goal being a treatment for age-associated conditions.
What productive effects might decelerating the ageing process have on society?