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Aging is associated with a significant decline of tissue repair and regeneration, ultimately resulting in tissue dysfunction, multimorbidity, and death. Salamanders possess remarkable regenerative abilities and have been studied with the prospect of inducing regeneration in humans and counteracting regenerative decline with aging. However, epimorphic regeneration, the full replacement of amputated structures, also occurs in mammals. One of the best studied models is digit tip regeneration, which is described for mice, and occurs in humans in a comparable manner. To accomplish regeneration, the amputated digit tip has to undergo three interdependent, overlapping steps: (i) wound healing without formation of a scar; (ii) formation of a blastema, a highly proliferative cell mass; and (iii) spatiotemporally regulated differentiation to generate a pattern similar to the original structure. Aging likely interferes with each of these steps. In this article, we provide an overview of the critical signaling pathways for regeneration, as revealed by investigating mammalian digit regeneration, the possible impact of aging on these pathways, and approaches to induce regeneration in the elderly. We hypothesize that with aging, increased Wnt signaling, NF-κB and tumor suppressor activity, and loss of positional information hampers regeneration. Knowledge about the impact of aging on regenerative mechanisms will enable us to safely activate endogenous regeneration in the elderly, and to generate a regeneration-permissive environment for cell therapies., (© 2018 S. Karger AG, Basel.)

Aging is studied either on a systemic level using life span and health span of animal models, or on the cellular level using replicative life span of yeast or mammalian cells. While useful in identifying general and conserved pathways of aging, both approaches provide only limited information about cell-type specific causes and mechanisms of aging. Stem cells are the regenerative units of multicellular life, and stem cell aging might be a major cause for organismal aging. Using the examples of hematopoietic stem cell aging and human pluripotent stem cell models, we propose that stem cell models of aging are valuable for studying tissue-specific causes and mechanisms of aging and can provide unique insights into the mammalian aging process that may be inaccessible in simple model organisms., (© 2016 S. Karger AG, Basel.)

Recently, the BM has been shown to play a key role in regulating the survival and function of memory T cells. However, the impact of aging on these processes has not yet been studied. We demonstrate that the number of CD4⁺ and CD8⁺ T cells in the BM is maintained during aging. However, the composition of the T cell pool in the aged BM is altered with a decline of naïve and an increase in T(EM) cells. In contrast to the PB, a highly activated CD8⁺CD28⁻ T cell population, which lacks the late differentiation marker CD57, accumulates in the BM of elderly persons. IL-6 and IL-15, which are both increased in the aged BM, efficiently induce the activation, proliferation, and differentiation of CD8⁺ T cells in vitro, highlighting a role of these cytokines in the age-dependent accumulation of highly activated CD8⁺CD28⁻ T cells in the BM. Yet, these age-related changes do not impair the maintenance of a high number of polyfunctional memory CD4⁺ and CD8⁺ T cells in the BM of elderly persons. In summary, aging leads to the accumulation of a highly activated CD8⁺CD28⁻ T cell population in the BM, which is driven by the age-related increase of IL-6 and IL-15. Despite these changes, the aged BM is a rich source of polyfunctional memory T cells and may thus represent an important line of defense to fight recurrent infections in old age.

During the lifetime of an adult organism, stem cells face extrinsic and intrinsic aging. Mesenchymal stem cells (MSC) can be expanded in culture, and the proliferation potential of individual cell isolates before growing senescent appear to be dependent on fitness and age of the donor, respectively. To date no molecular markers are available, which specifically reflect the degree of cellular aging in a population of MSC. Employing a genomic approach, we noticed that the gene encoding leptin receptor (also termed OB-R) is differentially regulated in MSC derived from aged donors as well as in MSC that had been stressed due to cultivation under hyperoxic conditions. We further observed that the leptin receptor transcript levels in primary MSC isolates are inversely correlated with the prospective number of generations that are ahead of these cells in culture, i.e., the number of population doublings that will occur in long term culture prior to cessation of growth due to replicative senescence. The MSC subpopulation, which exhibited distinctly elevated levels of leptin receptor or CD295 at the cell surface, is indistinguishable from dying cells. Considered together with the observation that primary MSC derived from healthy individuals showed proliferation capacities that declined at differentially increasing rates, we concluded that attenuation of MSC proliferation potential during aging greatly relies on the strictly increasing withdrawal of cells due to cell death.

Epimorphic regeneration is a multitissue regeneration process where amputation does not lead to scarring, but blastema formation and patterned morphogenesis for which cell plasticity and concerted cell-cell interactions are pivotal. Tissue regeneration declines with aging, yet if and how aging impairs epimorphic regeneration is unknown. Here, we show for the first time that aging derails the spatiotemporal regulation of epimorphic regeneration in mammals, first, by exacerbating tissue histolysis and delaying wound closure, and second, by impairing blastema differentiation and skeletal regrowth. Surprisingly, aging did not limit stem cell availability in the blastema but reduced osteoblast-dependent bone formation. Our data suggest that aging delays regeneration not by stem cell exhaustion, but functional defects of differentiated cells that may be driven by an aged wound environment and alterations in the spatiotemporal regulation of regeneration events. Our findings emphasize the importance of accurate timing of signaling events for regeneration and highlight the need for carefully timed interventions in regenerative medicine. [ABSTRACT FROM AUTHOR]

Objective: To examine the factors associated with healthy aging in a cohort of Mexican adults after a follow-up of 14 years.Study Design: Participants were part of a prospective cohort of the Mexican Healthy Aging Study (MHAS), from which we included 5142 individuals aged 63 years or more.Main Outcome: Healthy aging, defined as reaching age 77 or 90 without major chronic conditions or physical limitations.Measures: Information on age, education, marital status, smoking, alcohol consumption, physical activity, self-perceived depression, health conditions and history of age-related diseases was collected at baseline and follow-up.Results: Among the overall cohort, 57.8% experienced healthy survival to age 77 and 42.2% had died before age 77 or were undergoing normal aging. Participants with long-lived parents and who exercised had a lower risk of being non-healthy agers. Being overweight, obese or a smoker increased the risk of being a non-healthy ager. Physically active participants had increased odds of healthy aging at age 77 (OR: 1.17; 95% CI: 1.01-1.46) and at age 90 (OR: 1.5; 95% CI: 1.01-2.24). Depression had a negative relationship with healthy aging at age 90 (OR: 0.66; 95% CI: 0.45- 0.97). Maternal longevity was associated with healthy aging only at age 77 (OR = 1.34; 95% CI: 1.04-1.72).Conclusions: Our findings support the view that a combination of genetic and behavioral factors is associated with healthy aging. In accordance with findings in Caucasian populations, our data suggest for the first time that there might also be a genetic determinant for healthy ageing in Latin Americans. [ABSTRACT FROM AUTHOR]

Aging is studied either on a systemic level using life span and health span of animal models, or on the cellular level using replicative life span of yeast or mammalian cells. While useful in identifying general and conserved pathways of aging, both approaches provide only limited information about cell-type specific causes and mechanisms of aging. Stem cells are the regenerative units of multicellular life, and stem cell aging might be a major cause for organismal aging. Using the examples of hematopoietic stem cell aging and human pluripotent stem cell models, we propose that stem cell models of aging are valuable for studying tissue-specific causes and mechanisms of aging and can provide unique insights into the mammalian aging process that may be inaccessible in simple model organisms. [ABSTRACT FROM AUTHOR]

Mesenchymal stromal cells (MSC) have become a useful tool in curing graft versus host disease (GVHD) after transplantation. No information is presently available whether the immunosuppressive properties of this cell type are maintained in old age. It was therefore the aim of our study to analyze the immunoregulatory effect of MSC on peripheral blood mononuclear cells (PBMC) in old age. We studied the proliferation, activation and cytokine production of PBMC following co-culture with MSC from young (<30 years) and old (>61 years) donors. Our results demonstrate that MSC from elderly donors exhibit the same suppressive effects on T cell proliferation as their young counterparts, in both age groups T cell activation was not influenced by co-culture with MSC from young and elderly donors. With the exception of IL-6, cytokine production by unstimulated or stimulated PBMC was also not affected by MSC from either age group. IL-6 production was increased during co-culture of PBMC and MSC and was higher when MSC from elderly donors were used. After PHA stimulation, however, this age-specific difference was balanced and appeared even. As high IL-6 production is a prerequisite for an effective suppression of T cell proliferation, MSC can be considered a powerful tool for immunoregulatory therapies in old age. [ABSTRACT FROM AUTHOR]

Abstract: The prospective clinical use of multipotent mesenchymal stromal stem cells (MSC) holds enormous promise for the treatment of a large number of degenerative and age-related diseases. However, the challenges and risks for cell-based therapies are multifaceted. The risks for patients receiving stem cells, which have been expanded in vitro in the presence of xenogenic compounds, can hardly be anticipated and methods for the culture and manipulation of “safe” MSC ex vivo are being investigated. During in vitro expansion, stem cells experience a long replicative history and are thus subject to damage from intracellular and extracellular influences. While murine MSC are prone to cellular transformation in culture, human MSC do not transform. One reason for this striking difference is that during long-term culture, human MSC finally become replicatively senescent. In consequence, this greatly restricts their proliferation and differentiation efficiency. It however also limits the yield of sufficient numbers of cells needed for therapy. Another issue is to eliminate contamination of expanding cells with serum-bound pathogenic agents in order to reduce the risks for infection. A recent technical advancement, which applies human serum platelet lysates as an alternative source for growth factors and essential supplements, allows the unimpaired proliferation of MSC in the absence of animal sera. Here, we present an update regarding cellular senescence of MSC and recent insights concerning potential risks associated with their clinical use. [Copyright &y& Elsevier]

Aging as a process is paralleled by a variety of hematological alterations. Characteristic features are a diminished homeostatic control of blood cell production and a decline in immune functions. It is generally accepted that stromal cells play a basal role in hematopoiesis by providing survival and differentiation signals, by secreting cytokines, or through direct contact with hematopoietic stem cells, thereby supporting the generation and replenishment of hematopoi- etic progenitor cells (HPC). Here we demonstrated that HPC-related colony formation is positively influenced by mesenchymal stromal cells (MSCs) when grown in co-culture, in particular regarding the number of primary granulocyte/macrophage colony-forming units as well as with respect to the average size of the formed colonies. These effects were more pronounced when the MSCs originated from young donors than from old ones. Because leukemia inhibitory factor (LIF) plays an important role during hematopoiesis, properties of lin– Sca-1+ cells and MSCs derived from LIF-deficient mice (LIF–/–) were determined both ex vivo and in vitro. LIF–/– animals contain a significantly reduced number of lin– Sca-1+ cells, nevertheless the replating capacity of LIF–/– HPCs was found to be generally unchanged when compared to those from LIF+/+ animals. However, when cocultured with MSCs, LIF–/– lin– Sca-1+ cells exhibited comparable characteristics to HPCs derived from old wild-type animals. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells (MSC) are capable of differentiating into bone, fat, cartilage, tendon and other organ progenitor cells. Despite the abundance of MSC within the organism, little is known about their in vivo properties or about their corresponding in vivo niches. We therefore isolated MSC from spongy (cancellous) bone biopsies of healthy adults. When compared with the surrounding marrow, a fourfold higher number of colony-forming units was found within the tight meshwork of trabecular bone surface. At these sites, oxygen concentrations range from 1% to 7%. In MSC cultured at oxygen as low as 3%, rates for cell death and hypoxia-induced gene transcription remained unchanged, while in vitro proliferative lifespan was significantly increased, with about 10 additional population doublings before reaching terminal growth arrest. However, differentiation capacity into adipogenic progeny was diminished and no osteogenic differentiation was detectable at 3% oxygen. In turn, MSC that had previously been cultured at 3% oxygen could subsequently be stimulated to successfully differentiate at 20% oxygen. These data support our preliminary finding that primary MSC are enriched at the surface of spongy bone. Low oxygen levels in this location provide a milieu that extends cellular lifespan and furthermore is instructive for the stemness of MSC allowing proliferation upon stimulation while suppressing differentiation. [ABSTRACT FROM AUTHOR]

Abstract: The length of telomeres is believed to critically influence cellular aging processes and disease development. In order to reliably monitor telomere length and the corresponding cellular telomerase activity by optimized procedures, either based on flow cytometry or quantitative PCR technique, we here propose three commonly used cell lines, HEK293, K562 and TCL1301 as standards. In this contribution, efficient methods to determine mean telomere length of eukaryotic chromosomal DNA and determination of the corresponding telomeras activity are outlined. In particular, wide-range standard curves for a precise assessment of telomere length of genomic DNA by quantitative PCR technique are presented, measures, which greatly simplify the evaluation of respective functional roles of telomeres when studying biological processes such as disease progression and aging. [Copyright &y& Elsevier]