With aging, tissues in the body deteriorate - we all know that. However, what does that mean on a cellular level? Let's look into how physiological aging affect the blood system - an integral part to every organ and tissue in the body - from a recently published Nature journal article titled "Autophagy maintains the metabolism and function of young and old stem cells."
To give some background to the article, the blood system is comprised of many different blood cell types (like white blood cells, red blood cells, etc.), and they are all regenerated from hematopoietic stem cells (HSCs) (Figure 1). This makes them very critical for the proper maintenance and balance of the blood system. HSCs are rare in adults and are kept in low metabolic, quiescent (or dormant) state; in other words, they’re in hibernation state until they are called upon as needed to regenerate the blood system. Interestingly, the proper development of the blood system is also dependent on a process called autophagy. Autophagy can be thought of as the cell’s housekeeping system that keeps the cell clean for proper functioning; in more scientific terms, it is an intracellular degradation system that regulates the quantity and quality of organelles (functional units within a cell, can be thought of as a cell's internal organs) and macromolecules. With age, autophagy declines in many tissues, and this article is motivated in identifying how autophagy controls and affects HSCs’ function and aging.
Figure 1. Hematopoietic Stem Cell Differentiation. [Source]
For scientists, in order to study the function of something, one of the best ways is to take that out of the system and see what is affected. Similarly, to study the effect of autophagy, the study knocked out (or inactivated) the gene responsible for autophagy (the Atg12 gene) in adult HSCs in mice. The mice remained largely healthy, but had a skewed ratio of myeloid versus lymphoid cells in the blood, which resembled the myeloid-biased differentiation observed in old mice. HSCs with inactivated autophagy also had defective self-renewal activity resembling the functional impairment of old HSCs. From this, we can tell autophagy plays a role in maintaining the proper myeloid-lymphoid differentiation ratio as well as proper self-renewal activity.
Next, the effects of autophagy on the metabolism of HSCs were investigated. In terms of cellular metabolism, the mitochondria is likely the most important organelle that functions as the powerhouse of the cell, taking in nutrients and converting them to energy-rich molecules for the cell (Figure 2). HSCs deficient in autophagy were similar to old HSCs; their mitochondria powerhouses are more metabolically active as compared to those in young HSCs (demonstrated by increased cell size, increased oxygen consumption rates, and increased glucose uptake). These autophagy-deficient HSCs were also losing their quiescence and stemness (with accelerated differentiation into the myeloid lineage), which again resembled the deregulations characterized in old HSCs. Therefore, autophagy is essential for clearing metabolically activated mitochondria to allow HSCs to maintain in a more stem-like state.
Figure 2. Mitochondrion of a eukaryotic cell. [Source]
Finally, the study found that even though most blood cells showed a decline in autophagy with age, approximately one-third of old HSCs actually have increased autophagy levels, and these autophagy-activated old HSCs are the ones responsible for most of the blood repopulation. On the other hand, the autophagy-inactivated old HSCs are responsible for driving most of the blood aging phenotypes. However at this moment, it is unclear why some old HSCs have activated autophagy and others do not, but we do know that the level of autophagy activity is a determining factor on whether the HSC will be more young-like (being more regenerative) or old-like.
In summary, this paper demonstrated that autophagy is an essential process to remove activated mitochondria and controlling oxidative metabolism. These in turn are responsible for determining which genes get turned on/off (by changing external genetic patterns, also known as epigenetic modifications) for maintaining HSC stemness and regenerative potential. Thus, this study has identified a very specific cellular characteristic (you guessed it - autophagy) that can be directly targeted for improving old HSC function in preserving the health of an aging blood system. With further studies to better understand cellular aging, these findings would have large implications for rejuvenation therapies.