Fasting Reverses Age-Related Decline in Regenerative Capacity of Intestinal Stem Cells
Today I'll point out a demonstration of one of the many ways in which calorie restriction and fasting improve matters in our biology, in this case via improved stem cell function. As always it is worth bearing in mind that while forms of calorie restriction produce useful short term and long term healthy benefits in humans, they don't have anywhere near the same size of effect on life span as occurs in short-lived species such as mice. We didn't evolve to react as strongly to famines, as famines are typically a much shorter fraction of our life span in comparison to that of a mouse.
Stem cell populations, of different types for each variety of tissue in the body, support surrounding tissue by providing a supply of daughter somatic cells. As aging progresses, stem cell populations become ever less active, and this supply diminishes. Tissue function falters and eventually fails as a consequence. The evidence to date suggests that this decline is at least as much an evolved reaction to the state of damage in the body as it is dysfunction in the stem cells themselves. Numerous demonstrations show that, placed into a less damaged environment, old stem cells are just as active as young stem cells. Other lines of research have delivered signal molecules to induce old stem cells into greater activity in situ.
Is this safe? The consensus on why stem cell activity declines with age is that it balances mortality due to cancer versus mortality due to failing tissue function. Stem cells in old individuals do accumulate mutations and other forms of damage, while at the same time rising levels of inflammation and incapacity of the immune system lead to an environment that favors the development of cancer. Thus unrestricted cellular replication should have a higher risk of cancer. Evolutionary pressures have led our species to a long life span among mammals, but at the cost of a slow functional decline in later life.
Conversely, consider what has been discovered and achieved in the field of regenerative medicine: all sorts of methodologies to achieve enhanced stem cell activity. Consider the mice genetically engineered for greater levels of telomerase, in which their enhanced life span is probably mediated by increased levels of stem cell activity and tissue maintenance. The evolutionary balance appears to have a fair degree of wiggle room in which it is possible to build therapies to increase tissue maintenance without also needing to first repair the stem cells involved. The research community should still be aiming to repair and replace stem cell populations, of course - diminished numbers and cell damage become significant and problematic in very late life. This is a part of the SENS rejuvenation research agenda that, despite the high levels of funding and activity in the stem cell research community, hasn't yet made anywhere near enough material progress.
Fasting boosts stem cells' regenerative capacity
As people age, their intestinal stem cells begin to lose their ability to regenerate. These stem cells are the source for all new intestinal cells, so this decline can make it more difficult to recover from gastrointestinal infections or other conditions that affect the intestine. This age-related loss of stem cell function can be reversed by a 24-hour fast, according to a new study. The researchers found that fasting dramatically improves stem cells' ability to regenerate, in both aged and young mice.
Intestinal stem cells are responsible for maintaining the lining of the intestine, which typically renews itself every five days. When an injury or infection occurs, stem cells are key to repairing any damage. As people age, the regenerative abilities of these intestinal stem cells decline, so it takes longer for the intestine to recover. After mice fasted for 24 hours, the researchers removed intestinal stem cells and grew them in a culture dish, allowing them to determine whether the cells can give rise to "mini-intestines" known as organoids. The researchers found that stem cells from the fasting mice doubled their regenerative capacity.
Further studies, including sequencing the messenger RNA of stem cells from the mice that fasted, revealed that fasting induces cells to switch from their usual metabolism, which burns carbohydrates such as sugars, to metabolizing fatty acids. This switch occurs through the activation of transcription factors called PPARs, which turn on many genes that are involved in metabolizing fatty acids. The researchers found that if they turned off this pathway, fasting could no longer boost regeneration. They now plan to study how this metabolic switch provokes stem cells to enhance their regenerative abilities. They also found that they could reproduce the beneficial effects of fasting by treating mice with a molecule that mimics the effects of PPARs.
Acute fasting regimens have pro-longevity and regenerative effects in diverse species, and they may represent a dietary approach to enhance aged stem cell activity in tissues. Aging in lower organisms and mammals results in the attrition of stem cell numbers, function, or both in a myriad of tissues. Such age-related changes in stem cells are proposed to underlie some of the untoward consequences of organismal aging.
It has long been appreciated that fasting has a profound impact on aging and tissue homeostasis. Our data illustrate that a 24-hr fast augments intestinal stem cell (ISC) function through the activation of fatty acid oxidation (FAO), which subsequently improves ISC activity in young and aged mice. Fasting increases FAO in ISCs by driving both a robust PPAR-mediated FAO program in ISCs and by increasing circulating levels of triglycerides and free fatty acids (FFAs) that can be then used by cells to generate acetyl-CoA for energy. Although FAO is critical for tissues with high-energy needs like skeletal and cardiac muscle, little is known about the role of FAO in ISC biology. An important question is how does increased FAO boost ISC function.
Our data indicate that aged ISCs have a reduced capacity to utilize lipids for FAO. Consistent with this notion, aging has been associated with impaired mitochondrial metabolism and FAO in a number of tissues. Because the addition of palmitic acid (PA) or induction of FAO with PPAR-delta agonists largely restores aged ISC function in our organoid assay, one possibility is that ISCs rely on FAO and a shortage in cellular energy hampers old ISC activity.