Aging is a common phenomenon in nature, characterized by the accumulation of genetic damage throughout the life cycle—and by imbalances between DNA damage and repair, leading to genetic mutations. During this aging process, every cell and organ in the body experiences some degree of functional decline or deterioration.

For example, as we age, our skin loses its elasticity, wounds heal more slowly than they did in childhood, and fractures take much longer to mend. In short, the diminished regenerative capacity of damaged tissues or organs is the most prominent hallmark of aging.

The aging of the immune system stems fundamentally from the aging of HSCs.

Aging of the hematopoietic system manifests as Deterioration of the functions of the adaptive immune system and the innate immune system , the aging of these immune cells leads to heightened susceptibility to pathogenic microorganisms, reduced vaccine efficacy, and an increased risk of developing autoimmune diseases and hematological malignancies. Experiments involving HSC transplantation into T-cell and B-cell co-deficient mice demonstrated that age-related changes in the immune system's phenotype and function are primarily driven by functional alterations in HSCs during the aging process—and occur largely independently of thymic function.

Aging cells produce pro-inflammatory mediators and proteases, collectively known as the senescence-associated secretory phenotype (SASP). SASP factors recruit immune cells, including macrophages, neutrophils, natural killer cells, and T cells, and promote inflammation.

SASP-induced immune cell recruitment is a fundamental physiological process that eliminates unwanted cells and drives tissue remodeling essential for development and homeostasis. However, if these pro-inflammatory signals and inflammatory processes are not properly regulated, they can fuel pathological inflammation—for instance, senescent smooth muscle cells may exacerbate vascular inflammation, while the cellular senescence of endothelial and smooth muscle cells could also contribute to the persistence of inflammation in atherosclerosis. Moreover, macrophages play a critical role in clearing senescent cells. Age-related changes in the local microenvironment, meanwhile, can alter macrophage function within tissues, leading to age-associated declines in both phagocytic capacity and antigen-presenting ability.

Aging of hematopoietic stem cells

Most hematopoietic stem cells (HSCs) remain quiescent under dynamic equilibrium, rarely undergoing self-renewal through the cell cycle or differentiating into progeny cells. The process of hematopoiesis is tightly regulated by both intrinsic and extrinsic mechanisms, which together balance quiescence, self-renewal, and differentiation to ensure the stable maintenance of normal multi-lineage cells and facilitate systemic tissue regeneration.

As age increases, the myeloid HSC population expands and eventually becomes dominant within the overall elderly HSC pool.

The aging of HSCs is primarily evident in the following aspects:

1. B cell production declines significantly with age, and the diversity of the B cell lineage also diminishes, accompanied by reduced antibody affinity and impaired class switching.

2. The production of new T cells also declines with age, partly due to thymus degeneration;

3. NK cells exhibit reduced cytotoxic activity and cytokine secretion;

4. Although the number of myeloid cells has increased, their functional capacity has declined—for instance, neutrophils exhibit reduced migration in response to stimuli, and macrophages show diminished phagocytic activity.

5. Late-stage red blood cell production also decreases.

In fact, young bone marrow cells show considerably poorer engraftment when transplanted into older recipients compared to their performance in younger recipients. Although both aged and young hematopoietic stem cells (HSCs) released into circulation under granulocyte colony-stimulating factor (G-CSF) treatment exhibit similar mobilization effects, the bone marrow homing efficiency of aged HSCs is significantly reduced when these cells are intravenously transplanted into irradiated recipients. As a result, Donating bone marrow is not recommended for older adults. In transplantation studies, young HSCs consistently outperformed their older counterparts in terms of hematopoietic function. 。 

The most irreversible cause of HSC aging is linked to the accumulation of random DNA damage. Mice or patients with mutations in DNA repair-related protein-coding genes often exhibit hallmarks of premature aging in their hematopoietic stem cells (HSCs). Aging HSCs accumulate more DNA damage, likely due to elevated levels of reactive oxygen species (ROS) within the cells, which also trigger the production of genotoxic metabolic byproducts. Additionally, aged HSCs suffer from reduced DNA replication efficiency and transcriptional repression, a consequence of prolonged proliferative stress. While aging is traditionally thought to be primarily driven by the activation of p16—a key marker of senescent cells—some studies suggest that p16-mediated senescence has only a modest impact on maintaining homeostasis in aging HSCs.

High levels of ROS produced by mitochondria accumulate continuously in aging hematopoietic stem cells, ultimately impairing their function. Mitochondrial autophagy helps eliminate excess ROS, thereby reducing oxidative damage to mitochondria. Notably, a significant proportion of aged hematopoietic stem cells exhibit impaired autophagy levels—yet maintaining an adequate level of autophagic flux is crucial for preserving the youthful state of these cells.

Mesenchymal stem cells (MSCs) and endothelial cells are the primary components of the hematopoietic stem cell (HSC) niche surrounding blood vessels, significantly influencing HSC proliferation, differentiation, and aging. During the aging process, the bone marrow microenvironment undergoes numerous cellular and structural changes, and these alterations in the extracellular matrix can fundamentally impact stem cell function.

As mentioned above, the aging of hematopoietic stem cells with advancing age leads to immune system senescence, characterized by diminished phagocytic activity of immune cells, altered cell migration patterns, and reduced capacity to produce specific antibodies. Clinically, these changes may increase the incidence and mortality rates among older adults by elevating susceptibility to infections, malignant tumors, and autoimmune disorders. Given that both inflammation and aging can heighten the risk of leukemia, targeting and eliminating unwanted inflammatory senescence factors emerges as a promising strategy to preserve HSC function and immune health, thereby preventing declines in hematopoiesis and the emergence of malignant clones.

Compared to MSCs derived from young donors, mesenchymal stem cells from older donors exhibit significantly reduced proliferative capacity, with aged MSCs showing enlarged cell bodies due to senescence. Additionally, MSCs isolated from older donors display an increased number of SA-β-gal–positive cells—a marker of cellular aging. Moreover, the antioxidant ability of MSCs gradually declines as donor age advances. Age-related senescence also leads to decreased expression of several key membrane proteins in bone marrow-derived MSCs, including CD13, CD29, CD44, CD73, CD90, CD105, CD146, and CD166.

Interestingly, MSCs' ability to differentiate into adipocytes, osteoblasts, and chondrocytes is a fundamental characteristic of these cells—and it remains unaffected by age. Moreover, the efficiency of osteogenic differentiation doesn’t necessarily correlate with MSCs' broader multi-potential differentiation capacity.

Bone marrow MSCs derived from multiple donor sources exhibit individual variations in clonogenicity, cell size, proliferative potential, and immunosuppressive capacity. According to the clonal CFU-F assay, the number of bone marrow MSCs declines with age, impairing their ability to effectively promote the renewal of tissue progenitor cells. Additionally, adult bone marrow MSCs show a reduction in cell numbers, accompanied by increased levels of aging markers such as ROS, p21, and p53.

MSCs exhibit distinct age-related differences in cell proliferation, with aged or senescent MSCs showing declines in three key areas: cell quality, differentiation capacity, and migratory ability. Compared to cells isolated from young donors, aged MSCs also display additional hallmarks of cellular aging, such as reduced vitality, diminished proliferative potential, and impaired differentiation capabilities. Consequently, studies have shown that aged MSCs tend to deliver less effective clinical outcomes in therapeutic applications.

Obese individuals exhibit increased oxidative and metabolic stress in MSCs derived from adipose tissue, which directly impacts the mitochondria of these adipose-derived MSCs, leading to DNA damage, telomere shortening, reduced proliferation and stemness (manifested by decreased expression of NANOG, SOX2, and OCT4), as well as heightened apoptosis and cellular senescence.

Interestingly, the functional characteristics of adipose-derived MSCs isolated from different anatomical sites vary to varying degrees. Moreover, an obesogenic environment induces specific DNA methylation patterns, leading to changes in mitochondrial shape and number—and consequently affecting the functional properties of adipose MSCs. When co-cultured with young MSCs, macrophages exhibit markers characteristic of the M2 phenotype, such as Arg1 and IL-10, whereas macrophages co-cultured with aged bone marrow MSCs express TNF-α, a hallmark of the pro-inflammatory M1 phenotype. Additionally, age-related increases in adipogenesis may contribute to the SASP state, likely mediated by the activation of peroxisome proliferator-activated receptor gamma 2 (PPAR-γ2) and CCAAT/enhancer-binding protein (CCAAT/EBP).

BM-MSC-derived EVs from donors of different ages showed significant age-related differences in both their content and immunological characteristics. In a mouse model, extracellular vesicles (EVs) isolated from young MSCs contained higher levels of autophagy-related mRNA and sirtuins, enabling aged hematopoietic stem cells (HSCs) to regain functional capacity and vitality. In contrast, bone marrow MSCs from older donors released SASP, which promoted an inflammatory state in HSCs and ultimately impaired the function of younger HSCs.

MSC's age-related aging (senescence)

After undergoing a certain number of cell divisions, MSCs enter senescence, characterized morphologically by enlarged and irregular cell shapes, ultimately ceasing proliferation. Meanwhile, inappropriate culture conditions significantly accelerate this process. Aged MSCs exhibit reduced multipotency and impaired production of growth factors essential for tissue repair. Aging and oxidative stress significantly increase the miR-183-5p content in bone marrow-derived extracellular vesicles, leading to decreased cell proliferation, diminished osteogenic differentiation, and promoting MSC senescence by impairing heme oxygenase-1 (Hmox1) activity.

Aging MSCs exhibit reduced clonal formation and proliferative capacity, with a differentiation bias toward adipogenesis and diminished osteogenesis. Within the body, MSC senescence leads to reduced osteogenic capacity, contributing to age-related conditions such as osteoporosis. As a result, MSC aging is considered a key factor behind the impaired fracture healing observed with advancing age. This also partially explains why older adults are more prone to osteoporosis, as well as why fat cells accumulate in the bone marrow of elderly individuals.

The aging of MSCs within the body is considered a partial reason for the decline in tissue and organ function as the organism ages. Compared to young mice, an aging environment can suppress the function and potential of adult stem cells. Hyaluronic acid polysaccharides coated on cell culture surfaces help maintain the differentiation potential of human MSCs, enhance their proliferative capacity, stimulate telomerase activity, and delay cellular aging.

Therefore, the high hyaluronic acid content in the human body can serve as an initial indicator of the aging status of MSCs within the body. As people enter middle age, especially when hyaluronic acid levels in the subcutaneous layer decline, it not only leads to the appearance of skin wrinkles but also signals that MSCs throughout the body are gradually aging.

Fortunately, infusing healthy MSCs can help slow down the body's aging process. MSCs may detect mitochondria released by damaged somatic cells and subsequently mount a targeted response, initiating an adaptive repair mechanism that helps these cells recover. Moreover, fragments of healthy MSCs can be engulfed by the body’s immune cells, promoting the polarization of macrophages from the pro-inflammatory M1 type to the anti-inflammatory M2 type. Additionally, apoptotic bodies generated when infused MSCs undergo apoptosis in vivo stimulate the proliferation and renewal of endogenous MSCs, helping to restore youthful vitality to MSCs in the bone marrow. While the key regulators of MSC aging remain largely unidentified, they hold significant potential as therapeutic targets for combating age-related diseases and halting overall bodily senescence.

Interestingly, menopause and oophorectomy lead to a mild systemic inflammatory state and elevated plasma chemokine levels, while estrogen therapy helps suppress this condition. Therefore, for women, maintaining healthy, well-functioning ovaries is crucial. Mesenchymal stem cells (MSCs) can also help preserve ovarian function—and even offer a potential treatment for infertility caused by premature ovarian failure.