Wahlestedt M, Jan Pronk C, Bryder D. Concise review: Hematopoietic stem cell aging and the prospects for rejuvenation. Stem cell translational medicine 2015; 4:186-194.

Prepared by: Alexandra Condé-Green, Fall 2015.

LAYMAN ABSTRACT

Aging is an inevitable phenomenon where our organism composed of multiple cells is submitted to progressive changes and eventually failure. It’s associated with the inability to maintain the balance in organs and tissues that are submitted to stress or injury. The resident stem cells in our body, the hematopoietic system that produces blood are also linked to the aging process. This results in a decrease in the adaptive immune response.

The authors reviewed different theories related to aging of the hematopoietic system. The most common related causes are decrease production of B and T lymphocytes with a predominance of myeloid cells resulting in an increase in myeloid leukemia with age. The hematopoietic stem cells (HSCs) have longer half-life than other cells. They have more telomerase enzyme therefore negligible telomere shortening. However they are more susceptible to DNA damage, mitochondrial dysfunction, accumulation of damaged proteins and toxic metabolites than other cells. They are also more susceptible to oxidative stress and insults from the environment. The gene expression patterns of HSCs are altered with age and they seem to be the main modifications responsible for their aging process.

Different ways to address or potentially revert the HSC aging process are reviewed. Since HSC aging is multifactorial, some of the causes have been addressed to therapeutically reverse the process. Overexpression of telomerase to lengthen the telomeres, repair of DNA and mitochondrial DNA have not significantly reverted the process. Drugs targeting the gene expression patterns of HSCs such as the alteration of loci, the disruption of cell polarity, have shown some degree of rejuvenation of HSCs.

Knowing all these theories and potential target drugs, is encouraging as it shows the potential use of exogenous agents to modulate HSC aging. The objective in doing so is not to prolong life per se, but rather to improve the quality of life and achieve immunocompetence.

SCIENTIFIC ABSTRACT

Aging of our multicellular organism is considered a multi-parameter process characterized by progressive changes and failure of various organs. It’s associated with the inability to appropriately maintain organ and tissue homeostasis or to return to homeostatic conditions following stress or injury.  Tissue resident stem cells are also linked to the aging process and so is the immune system. Thus the hematopoietic system is submitted to alterations at multiple stages with resultant decrease in the adaptive immune response. The authors present a review of theories related to hematopoietic stem cell (HSC) aging and the possible ways to address or potentially revert this process.

The decrease in the adaptive immune response is due to altered effector cell function but also a decrease production of naïve B and T lymphocytes with predominance of myeloid cells referred to as myeloid skewing or bias, with resulting increase of myeloid hematological diseases with age. XXX

Hematopoietic cells because of their long life span have negligible telomere shortening and detectable levels of telomerase enzyme. However they are more subject to increasing amounts of DNA damage, than other cells. They are prone to intracellular alterations, including damage of mitochondrial DNA as a consequence of replicative errors, oxidative stress and environmental insults. The gene expression patterns of young HSCs become altered with age. Components involved in chromatin organization and epigenic maintenance are dysregulated. There is altered distribution of DNA methylation, altered expression of key loci, disrupted cell polarity, histone modifications. The mammalian target of rapamycin pathway (mTor) that integrates multiple signals from nutrients, growth factors and oxygen to regulate critical cellular functions, is increased in aged HSCs. These cell intrinsic alterations are prominent in aged HSCs suggesting that altered transcriptome and epigenome are main contributors of immunoaging.

Some of these causes at the origin of HSC aging have been addressed in order to therapeutically reverse the aging process. Overexpressing the enzyme telomerase to lengthen telomeres, tentative of DNA repair have not been the most successful as these were not considered primary causes of HSC aging. Normalization of dysregulated loci, reprogramming aged HSCs and progenitor cells into induced pluripotent cells (iPS) and re-differentiation into HSCs in vivo using blastocyst complementation resulted in HSCs that functioned as their young counterparts.

Thus, HSC aging appears to be reversible and strongly associated with a transcriptional and epigenetic drift. Therefore, therapeutics targeting specific altered loci, disrupted cell polarity, mTOR inhibition represent an avenue for reversal of HSC aging. The use of already clinically used epigenetic drugs, such as the histone deacetylase inhibitor valproic acid, might rejuvenate age dysregulated loci, but to date only partial rejuvenation has been reached. Also, the use of these non-specific drugs could potentially lead to opposite outcomes in other organs as seen with Growth differentiation factor 11 (GDF-11) that appears to have rejuvenation actions in brain and heart but inhibitory actions on erythroid development.

The process of aging is multifactorial. Thus, inhibition or reversal is not without challenges and will require modulation of one or more regulators of tissue homeostasis, which comes at risk. An understanding of the theories as well as the potential target areas, is encouraging as it shows the potential use of exogenous agents to modulate HSC aging. The objective is not to prolong life per se, but rather to improve quality of life and achieve immune competence.

References:

Oh J, Lee YD, Wagers AJ. Stem cell aging: mechanisms, regulators and therapeutic opportunities. Nature Medicine 2014; 20(8):870-880.