Our bodies constantly repair and regenerate tissue. The body continually creates new cells based on stem cells in various types of tissue that can perform the highly specialized functions the tissue requires. When we age or when our body is exposed to chemotherapy, declining function of stem cells impairs this regeneration of tissue. Researchers now believe that a gene first discovered in fruit flies may be the key to maintaining stem cell function. Ultimately, this may enable us to live longer.
The telltale signs of ageing include our muscles aching a little longer and wounds healing a little slower. Then there are signs we only notice when we get sick. In the bodies of young people, stem cells easily withstand everyday wear and tear and replace damaged cells with new ones. However, as we age, the regenerative capacity of stem cells declines. A new study identifies one of the key functions for maintaining the stem cell’s ability to repair tissues.
“The regenerative potential of the lining of the human intestines – intestinal epithelium – declines with age because of damage to both the stem cells and their niche. The apparent reason why the signals required to maintain this regenerative potential change is increased production of the Notum enzyme. When we inhibited it, the cells recovered their regenerative capacity. We hope that we can use this knowledge to help people age better and to help people treated for cancer to recover faster and more effectively,” explains Pekka Katajisto, Principal Investigator, Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
Wingless fruit flies
A decline in stem cell function impairs tissue regeneration during ageing. However, the intestines are one of the types of human tissue that regenerates most rapidly. Previous experiments have shown that the intestines of young mice have effective regenerative potential. Unfortunately, that potential diminishes with age, and previous research on the intestines of old mice has shown that they regenerate more slowly after radiation-induced damage. Since this indicated reduced stem cell activity, the researchers decided to investigate the mechanisms of the intestinal epithelium of mice.
“Examining the gastrointestinal system showed that ageing is associated with problems in both the stem cells and their niche. A decline in wingless-related integration site (Wnt) signalling was especially noteworthy. In young tissue, these signals maintain the regenerative potential of the stem cells and thus restore damaged tissue, but this function declines with ageing because the body produces Notum, an extracellular Wnt inhibitor.”
Researchers discovered the role of Wnt signalling in the development of cells and fetuses more than 30 years ago when they found that genetic mutations affecting proteins in the Wnt signalling pathway in fruit flies produced highly abnormal wingless fruit flies.
Our experiments show that Notum has the same effect in humans and mice. When we inhibit Notum or otherwise restore Wnt signalling, the stem cells retain the ability to regenerate. Our results thus indicate that, if the expression of Notum can be artificially controlled, we may be able to promote the regeneration of ageing or damaged tissue.
Dreaming of living longer
The researchers’ ultimate goal is to understand why stem cell function declines during ageing, which would thereby enable the researchers to develop stem cell–based strategies targeting ageing-related diseases and disorders. In this respect, the researchers made another important discovery a few years ago when they found that some stem cells divide asymmetrically, creating both a new and an evolving stem cell in a predetermined way.
“Since accumulated cell damage is the main cause of ageing, asymmetric division enables age-associated damage in the stem cell line to be reduced if we can ensure that the damaged parts end up in the differentiating daughter cells, which die at some point, rather than the stem cell, which will form the basis for numerous future cells.”
The researchers are studying the biology of ageing and trying to understand the role of stem cells in each type of tissue and the molecular mechanisms underlying impaired regeneration. They hope to learn to understand the basic mechanisms of cell-level ageing and thus find new ways of combating loss of muscle function among older people or helping people to survive toxic treatments such as chemotherapy.
“The main focus is improving the quality of life in the last years of people’s lives. Nevertheless, we cannot help but dream about being able to change the ageing process itself some day. We think that humans can live for about 120 years if they have perfect genes and some luck and eat very little. However, there is no biological reason why we cannot live longer. There are already many examples of other animals that live much longer, and the more we can improve how we take care of our stem cells, the longer we can live.”
“Notum produced by Paneth cells attenuates regeneration of aged intestinal epithelium” has been published in Nature. Pekka Katajisto gave a lecture in October 2019 at the Copenhagen Bioscience Conferences – a Novo Nordisk Foundation initiative launched in 2007.