Urolithin A Supplementation Improves Mitochondrial Function and Hematopoiesis in Mice

A number of supplement-based approaches have been demonstrated to modestly improve mitochondrial function with age. This includes the various ways to increase NAD levels using vitamin B3 derivatives, mitochondrially targeted antioxidants such as SkQ1, MitoQ, and SS-31, and other compounds such as urolithin A for which the mechanism causing improved mitochondrial function is not as well determined. There is an argument to be made that all of these compounds work because they in some way improve the operation of mitophagy, a mitochondrial quality control mechanism that senses worn and damaged mitochondria, before directing them to a lysosome for recycling. That sensing is complicated and incompletely understood, which makes it challenging to determine what exactly is going on under the hood.

We do know that mitochondrial function and mitochondrial quality control are improved by the practice of calorie restriction, as well as by the exercise needed to maintain physical fitness. This might lead us to suspect that these approaches to improving mitochondrial function will have smaller effects on life span in long-lived humans than in short-lived mice, as that is exactly what happens in the case of calorie restriction. Meanwhile, we have no intuition as to the size of the outcomes that might be achieved via complete replacement of mitochondria, which is to my eyes the most promising approach to mitochondrial rejuvenation, or via allotopic expression, producing backup copies of mitochondrial DNA, or via partial reprogramming, which resets problematic gene expression changes that occur with age and impair aspects of mitochondrial function.

New study: reversing aging in the blood stem cells and the immune system

The aging process is often accompanied by a decline in the proper functioning of the hematopoietic and immune systems, making older adults more susceptible to infections, blood disorders, and even tumor development. A new study focused on a key player in the blood system - hematopoietic stem cells (HSCs). These cells are responsible for generating various types of blood cells, playing a critical role in maintaining a healthy immune system. As we age, HSCs experience a decline in their ability to regenerate blood and show a preference for a specific type of cell lineage, which contributes to immune system dysfunction.

By introducing a natural compound called Urolithin A, which targets mitochondria - the energy powerhouses of cells - researchers were able to reverse the decline in HSC function. Mitochondria abnormalities were identified as a contributing factor to the aging of HSCs. Urolithin A acted as a mitochondrial modulator, effectively restoring the mitochondrial function within HSCs. Urolithins are not found in food; however, their precursors are. Urolithin A is the result of transformation of ellagic acids and ellagitannins by the gut microflora in humans.

The most interesting finding of this preclinical study was that this intervention not only rejuvenated the blood reconstitution capability of older HSCs but also improved immune system function in aged mice. When Urolithin A was incorporated as a dietary supplement, it not only revitalized the immune system's lymphoid compartments but also enhanced overall HSC performance. This translated to an improved immune response against viral infections, showcasing the potential of Urolithin A to combat age-related immune system decline.

Induction of mitochondrial recycling reverts age-associated decline of the hematopoietic and immune systems

Aging compromises hematopoietic and immune system functions, making older adults especially susceptible to hematopoietic failure, infections and tumor development, and thus representing an important medical target for a broad range of diseases. During aging, hematopoietic stem cells (HSCs) lose their blood reconstitution capability and commit preferentially toward the myeloid lineage (myeloid bias). These processes are accompanied by an aberrant accumulation of mitochondria in HSCs.

The administration of the mitochondrial modulator urolithin A corrects mitochondrial function in HSCs and completely restores the blood reconstitution capability of 'old' HSCs. Moreover, urolithin A-supplemented food restores lymphoid compartments, boosts HSC function and improves the immune response against viral infection in old mice. Altogether our results demonstrate that boosting mitochondrial recycling reverts the aging phenotype in the hematopoietic and immune systems.