Longevity Briefs: Using Engineered Stem Cells To Reverse Brain Ageing

Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

Stem cells are cells capable of developing into multiple different cell types and are vital for maintaining and regenerating damaged tissue. When muscle tissue is damaged, for example, dormant stem cells are roused into action and multiply to form new muscle tissue, blood vessels and so on. As we age, however, the ability of stem cells to renew themselves declines, and an increasing number of them enter a state called senescence in which they are unable to divide. This ‘stem cell exhaustion‘ is one of the hallmarks of ageing and a likely contributor to many age-related diseases.

We could potentially reverse stem cell exhaustion using stem cell therapy – generating new stem cells from a patient’s own cells and introducing them back into ageing tissues. Yet as we covered in a recent discussion of stem cell therapy and the challenges it faces, stem cells often don’t behave in the desired way when introduced into the ‘hostile environment’ of diseased tissue, and ageing tissue is no exception. The same conditions that turned an organism’s stem cells senescent in the first place will rapidly cause senescence in newly introduced therapeutic stem cells. In this study, researchers show how this problem could potentially be overcome, by genetically enhancing the activity of a ‘longevity gene’ known as FOXO3.

The discovery:

In the study, which lasted 44 weeks in total, researchers delivered human mesenchymal progenitor cells (MPCs, a type of stem cell commonly used in research due to their ability to differentiate into many different cell types) to 19-23 year-old macaque monkeys (which are considered to be ‘aged’). Some monkeys received a sham treatment as a control, some received normal human MPCs (‘wild type’ cells, WTCs) while another group received MPCs that had been genetically altered to help maintain the activity of a gene called FOXO3. The rationale for this was that FOXO3 is important for resistance against cellular stress, which can turn cells senescent. FOXO3 also helps keep stem cells in a non-dividing (but non senescent) state, so that they don’t prematurely divide unnecessarily and deplete the stem cell pool. Before administering them to the monkeys, the researchers confirmed that these cells were resistant to senescence and so called them senescence-resistant cells (SRCs).

These SRCs appeared to reverse many aspects of brain ageing in the treated monkeys compared to the controls, in contrast to the WTCs (the unmodified stem cells) which had less and in some cases no discernible effect. SRC treated monkeys performed better on several cognitive tests, had increased cerebral cortex thickness and reduced markers of Alzheimer’s disease (amyloid-β aggregates and Tau protein).

The researchers also found that both SRCs and WTCs had beneficial effects on the immune system, leading to reduced senescence among white blood cells and reduced markers of inflammation, but again SRCs appeared to have a greater impact.

Finally, the researchers attempted to estimate the biological age of 61 different tissues using RNA sequencing. This is a technique that attempts to estimate how biologically old a tissue is based on patterns of gene expression. They estimated that SRCs reduced biological age by an average of 3.3 years across all tissues, compared to 2.8 years by WTCs.

The implications:

This research suggests that we might be able to improve the impact of stem cell therapy on ageing by enhancing the expression of FOXO3, helping the stem cells to resist the stresses of an aged environment and avoid becoming senescent. In our article covering the challenges faced by stem cell therapies, we also discussed how exosomes – tiny packages full of molecular signals released by cells – were actually responsible for many of the benefits associated with stem cells. The researchers in this study found that exosomes from SRCs conferred many of the same benefits as the SRCs themselves when used to treat mouse and human cells. If further research can confirm that exosomes from SRCs work better than exosomes from WTCs, this would be good news for safely translating these findings into humans. This is because while FOXO3 acts as a tumour suppressor in normal cells, it may also enhance survival of cancer cells if cancer does occur. We might therefore need to be cautious about putting cells with altered FOXO3 activity into humans given that stem cells becoming cancerous is already a concern with stem cell therapy. This is not so much a concern with exosomes, as there are no cells for cancer to occur in.