Aging Associated with Stem Cell Exhaustion and Altered Intercellular Communication

Old cells can malfunction, and the body has macrophages that remove them from tissue. The old cells are replaced by new and healthy cells derived from stem cell niches. The replacement process keeps the number of cells in a tissue balanced over the long run. In the aged body, this homeostasis sometimes breaks down [2]. Here we discuss two different factors that modify such a delicate balance: namely stem cell exhaustion and altered intercellular communication. These factors are hallmarks of aging [3].

Stem cell exhaustion

Stem cells are a tiny fraction of the trillions that constitute the adult human body. They are a rare cell type that can self-renew and differentiate as long as the organism is alive. Stem cells are defined clonally at a single-cell level according to their developmental potency and renewal ability [4]. Three main types are; (1) totipotent stem cells (TSCs), (2) embryonic stem cells (ESCs), and (3) somatic stem cells. TSCs are capable of differentiating into any cell type but they have a limited self-renewal capacity. Unlike TSCs, ESCs can propagate in culture indefinitely [4]. Somatic stem cells are characterized by a restricted differentiation to the particular tissue where they reside.

When an organism gets old, the stem cells are less apt to self-renew and differentiate, thus impairing the regenerative potential of body tissues. Somatic stem cells appear to age with the person thus declining in functional ability [5]. This seems related to the unique character of these cells to asymmetrically divide and yield unequal daughter cells. One of the daughters maintains the stemness property of self-renewal while the other becomes more differentiated [6].

Studies with aged mice have shown that the activity of hematopoietic (blood) stem cells (HSCs) declines with aging [7]. This decline also occurs in healthy humans as they age[8]. Such a decline is correlated in mice with an overall reduction in the cell cycle activity and accumulation of DNA damage. In addition to DNA damage, overexpression of inhibitory cell cycle proteins and telomere shortening are important factors that lead to decreasing stem cell activity with aging.

For long-term maintenance of the organism's wellbeing, the replacement of old and/or damaged cells must keep pace with the proliferation of stem cells, a condition termed quiescence. Disruption of quiescence by excessive proliferation leads to the exhaustion of the tissue niche of stem cells and premature aging, as shown in Drosophila intestinal stem cells [9] and HSCs from p21 null mice [10]. Interestingly, disruption of quiescence in the aged muscle cell niche arises by an increase in fibroblast growth factor FGF2 signalling. This leads to stem cell depletion and diminished regenerative capacity, an outcome that could be prevented by blocking this signaling [11].

The regenerative capacity for different tissues (muscle, brain, bone) appears determined by the age of the niche rather than that of the proper stem cell [6] . Accordingly, effective tissue regeneration can be promoted by “seeding” old niches with stem cells derived from young ones. Conversely, aged niches inhibit the regenerative capacity of young stem cells, thus demonstrating the key role of the extracellular microenvironment in regulating the performance of stem cells. Additionally, parabiosis studies in rodents have shown that it is possible to rejuvenate old mice by transferring the "young phenotype" to the tissue or blood plasma. This constitutes a proof-of-concept study on animals that could be extrapolated to humans within ethical limits. It is possible to induce specific differentiation pathways by manipulating the microenvironment in vitro [12].

The ability of stem cells to self-renew and differentiate makes them a unique biological tool for possible human tissue repair and rejuvenation and for other medical applications such as transplantation and cell-based therapies. The discovery that differentiated stem cells can be returned to their original pluripotent state and the known process of laboratory reprogramming of cells opens up possibilities to develop safe therapies for a wide range of human afflictions [12].

Altered intercellular communication

Within tissues, cells communicate with each other through a plethora of signaling mechanisms. This communication allows the cells to respond to microenvironmental changes and thereby to take action to preserve homeostasis and tissue functioning. Human aging brings a series of changes that impair cellular communication. For instance, neurohormonal signaling strength declines as a person gets older, as does the capacity of the adaptive immune system.

Aging appears to dysregulate the body's immune surveillance system, creating a proinflammatory age-associated phenotype termed inflammaging [13]. The activation of this phenotype triggers stimulation of the NLRP3 inflammasome and other pro-inflammatory pathways, which results in increased production of inflammatory cytokines (IL-1b, TNFa), and IFNs, finally cell death[13].

The importance of inflammation in aging is further shown by the overactivation of NF-kB signaling. Expression of NF-kB pathway inhibitors induces the young phenotype in aged transgenic mice and decreases the aging rate in mouse models[3]. Furthermore, inflammation triggers increased NF-kB signaling in the mouse hypothalamus leading to a decrease through the body of secretion of gonadotropin-releasing hormone. Less of this hormone in the body correlates with aging-associated body changes, including bone fragility, muscle weakness, and reduced neurogenesis. Conversely, more hormone prevents aging-impaired neurogenesis and diminishes the aging rate in mice [14].

Likewise, interference in the expression of inflammation-associated genes by mRNA decay factor AUF1 causes the inflammatory cytokine response to shut down. AUF1-deficient mice show a profound cell senescence and rapid premature aging that can be reversed by re-expression of this factor [15]. Similar effects are obtained by down-regulating inflammation-related genes by modifying NF-kB subunits and other cytokines with specific sirtuins deacetylases [3].

Aging cells affect their surroundings by releasing bioactive molecules, including reactive oxygen species that cause DNA damage in neighbor cells, and inducing them to senesce.

It is possible to intervene at the molecular level to ameliorate the impaired intercellular communication that arises with age. Rejuvenating tissues and organs by the transference of the "young phenotype" cells may form the basis of future technologies aiming to cure diseases, decelerate aging, and prolong human life.


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