Hematopoietic Cells are Impacted by Cellular Senescence in Old Humans

Hematopoietic stem and progenitor cell populations are responsible for generating immune cells. Their decline is one of the causes of immune failure with age, as the pace at which new immune cells are created falters. There are other equally important issues in immune aging, such as the atrophy of the thymus, where T cells of the adaptive immune system mature, and the accumulation of malfunctioning immune cells in older individuals, but we'll put those to one side for this discussion.

Stem cell decline with aging is a complicated business with many contributing causes, and the relative importance of those causes seems to differ between populations and tissues. Few stem cell populations are very well studied when it comes to asking why exactly it is that they decline in activity with age. Those that are, such as muscle, hematopoietic, and neural populations all seem to be quite different. Muscle stem cells decline in activity but, given the right signals, appear quite ready to go back to work with minimal signs that they are greatly impacted by damage. Hematopoietic stem cells do appear to be more damage-limited, however.

In this open access paper, the authors look at the detrimental impact of cellular senescence on hematopoietic cells, and thus on the immune cells that they produce. Cellular senescence is a reaction to damage or excessive replication; senescent cells cease to replicate, and most such cells self-destruct or are destroyed by the immune system. Some linger, however, and the harmful, inflammatory mix of signals that they generate are implicated as a cause of degenerative aging. Studies in mice show that removing senescent cells improves health and extends life span. There are also populations of cells that show some of the markers and behaviors of senescence, but have yet to be definitively classified as senescent - nothing is simple when it comes to cellular biology. This pseudo-senescence or maybe-senesence may be the case here; more research will determine whether or not this is the case.

Elderly human hematopoietic progenitor cells express cellular senescence markers and are more susceptible to pyroptosis

Aging is associated with an increased prevalence of multiple comorbidities, including infectious and malignant diseases. Many of these disorders are thought to stem from old-age-related immune decline. Increasing efforts to characterize the immune system of elderly people in recent years have revealed that most immunocompetent cell compartments present profound quantitative as well as qualitative impairments. The cause of these impairments can vary, and is often related to the exhaustion of the cells or their functions over time in inflammatory settings.

The majority of mature blood cell compartments need, therefore, to be continuously replenished or replaced, which is the role of hematopoietic progenitor cells (HPCs) and, ultimately, hematopoietic stem cells (HSCs). While the self-renewal and differentiation potential of stem cells, along with their blood cell reconstitution capacity, have long been considered as infinite, increasing evidence indicates that this is not the case. Under conditions of stress, HSCs eventually exhibit several functional defects, including a diminished regenerative and self-renewal potential. Loss of stem cell activity is therefore a likely mechanism of impairment common to many mature cell types, thus representing a central cause of immune-competence decline.

Most studies on HSC aging have been carried out in mouse models, and have highlighted extrinsic and intrinsic factors affecting the function of HSCs. A recent study reveals that loss of autophagy in most HSCs from aged mice causes an activated metabolic state, which is associated with accelerated myeloid differentiation, and impairs HSC self-renewal activity and regenerative potential. In humans, much less information is available on the aged HSCs, due to the limited and challenging access to bone marrow samples of elderly humans, the niche of HSCs. Reduced transplantation success in patients receiving HSCs isolated from older (45 years and above) donor bone marrows indicates that human HSC regenerative capacity also declines with aging.

We performed here a comprehensive study of blood HPCs, as an alternative to bone marrow HSCs, to overcome the constraint of sample availability from elderly adults. Based on phenotypic analyses, in vitro T lymphocyte differentiation assays, and gene expression profiling of circulating HPCs from aged subjects, we demonstrate impaired lymphopoiesis and active cell cycling of HPCs with aging, and provide insights into their functional impairments. Our findings reveal that, while mobilized, elderly HPCs present evidence of cellular senescence and increased cell death by pyroptosis. Reduced telomere length and telomerase activity in old HPCs may affect the properties of their progeny, such as mature T lymphocytes. This pre-senescent profile is characteristic of the multiple intrinsic and extrinsic factors affecting HPCs in elderly individuals and represents a major obstacle in terms of immune reconstitution and efficacy with advanced age.

Comments

It's not nearly as complicated as this makes out. HSCs have a limited proliferative capability. And senescence is not a black and white thing. Yes at the extremes a senescent cell cannot divide. But cells exist in a continuum from young to old, and from fully functional to completely senescent. Most cells exist some where in-between. That's might take on this, anyways.

Posted by: Mark at July 18th, 2018 4:41 PM

While bone marrow is active in pre-adults, in adults the bone marrow is not active in the large long bones of the body as far as I can tell from the limited papers I have read on the subject. It seems to me we should have active research effort to rejuvenate the bone marrow of the large long bones of adults as is going on in research circles for rejuvenation of the thymus gland. One might first try to find out if those having a very active lifestyle still have full or partial bone marrow activity in their adult populations. I am thinking of marathoners, soccer players and perhaps older basketball players. Perhaps with rejuvenation of the bone marrow of the large long bones of the body, we could also have reduction of osteoporosis, and maintenance of blood vessels and vessel endothelium of bones in older adults, as well as better maintained stem cell pools in the bone marrow and much better immunity in the elderly.

Posted by: Biotechy Marcks at July 21st, 2018 10:29 AM

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