Fight Aging! Newsletter, June 21st 2021

Several recent publications, including the one entitled "What if there is no such thing as aging?", have brought out an astonishing trend: the mere existence of biological aging is being questioned. The title reiterates the famous proposition "There is no such thing as aging and cancer is not related to it", and the paper suggests that the same is relevant to the other age-associated conditions: "...we are not studying a single biological phenomenon, but an assortment of loosely related processes that we find convenient to lump together"; ultimately, "... the concept of aging does not reflect any underlying biological reality".

Being intentionally provocative, the paper does however reflect the trend, which is developing, paradoxically, in parallel with the increasing prevalence of aged people in the world and with the recently emerged discipline called "geroscience". According to the geroscience agenda, the best way to combat the most prevalent age-associated conditions, such as atherosclerosis, cancer, type II diabetes, and neurodegeneration, is to target their common risk factor rather than each of the conditions specifically. The common risk factor is aging.

Apart of that the very practice of piling up of newly invented scientific disciplines and respective terms is questionable, a problem with the geroscience agenda relates to the feasibility of evaluating the benefits of its implementation. The benefits of targeting of a disease may be evaluated, based on its commonly accepted definition (diagnostic criteria), as a decrease in the incidence of cases recognized according to this definition. Can we decrease the incidence of aging otherwise than by making people dead before they get old? Any answer to this question depends on the criteria used to distinguish (i) aging from all the rest that may occur to living bodies and (ii) living bodies from all other kinds of bodies, in other words, on the definition of (biological) aging. The lack of consensus on the definition of aging is long recognized and has recently been highlighted by asking several basic questions about aging to recognized authorities in aging research. Answers to each of the questions differed up to antipodal extremes.

Based on several scores of definitions found in the most highly cited (that is the most representative and influential) papers on aging, the following features commonly used to define aging have been distinguished: (1) structural damage, (2) functional decline, (3) depletion of a reserve required to compensate for the decline, (4) typical phenotypic changes or their cause, and (5) increasing probability of death. Noteworthy, these characteristics are not really five definitions of aging, but rather five defining features of aging. This the above inventory to the kind of definitions that in philosophy of science is known as "nominal" and is opposed to "real"

By its nominal definition, water is a colorless and odorless liquid having defined specific gravity, viscosity etc. By its real definition, water is a compound comprised of two hydrogen atoms and one oxygen atom connected in a certain order. Noteworthy, the real definition is senseless for people ignorant of atoms. Likewise, the nominal definition of aging as a set of observable features should be supplemented, if not replaced, with its real definition. The latter is suggested here to imply that aging is the product of chemical interactions between the rapidly turning-over free metabolites and the slowly turning-over metabolites incorporated in macromolecules involved in metabolic control.

The phenomenon defined in this way emerged concomitantly with metabolic pathways controlled by enzymes coded for by information-storing macromolecules and is inevitable wherever such conditions coincide. Aging research, thus, is concerned with the elucidation of the pathways and mechanisms that link aging defined as above to its hallmarks and manifestations, including those comprised by its nominal definitions. Esoteric as it may seem, defining aging is important for deciding whether aging is what should be declared as the target of interventions aimed at increasing human life and health spans.

Aging increases the risk for developing Alzheimer's disease (AD). Pathological hallmarks of AD include abnormal deposits of extracellular beta amyloid (Aβ) plaques and intracellular neurofibrillary tangles, which are proposed to impair synaptic function to foster progressive cognitive impairment. Although aging and AD undeniably share a number of common features, such as oxidative stress, mitochondrial impairment, bioenergetic, and metabolic shifts, AD is not the inevitable co-morbidity of aging. This escape from AD arouses hope that anti-aging interventions could decelerate aging switches for AD dementia.

Our environment, lifestyle, stress, physical activity, and habits all modulate epigenetic control of gene expression for continuous environmental tracking. Age-related redox stress, often measured as oxidative stress in aging and AD, launches a global switch in the epigenetic landscape, widely affecting methylation, histone modification, and noncoding RNA regulation, to further drive downstream metabolic and energetic shifts.

According to a modified amyloid cascade hypothesis, amyloid-mediated oxidative stress triggers a cascade of downstream effects including mitochondrial dysfunction, excitotoxicity, synaptic loss, and neuroinflammation. However, the failure of anti-amyloid and anti-inflammatory therapy in clinical trials allows us to entertain other causal possibilities including an age-related oxidative redox shift as an upstream switch that changes amyloid processing, deposition, or clearance. Intriguingly, some resilient older individuals present with similar loads of Aβ and tangles compared to AD cases without experiencing dementia.

Further studies in resilient brains point out distinct upregulation of anti-inflammatory cytokines in entorhinal cortex, increased expression of neurotrophic factors and reduced expression of chemokines linked to microglial recruitment, which all suggest activated neuroglial inflammation in non-resilient AD. Since inflammation is switched on by an oxidative redox state, normal microglia that selectively remove excitotoxic synapses could be over-activated toward inflammatory neurodegeneration in AD. Suitable redox markers could enable measured redox therapies to decelerate inflammation and the neurodegenerative cascade.

We did a phase 2b and a phase 3 double-blind, randomised, placebo-controlled trial in adults aged at least 65 years enrolled in New Zealand, Australia, and the USA at 54 sites. In the phase 2b trial, patients were aged 65-85 years, with asthma, type 2 diabetes, chronic obstructive pulmonary disease (COPD), congestive heart failure, were current smokers, or had an emergency room or hospitalisation for a respiratory tract infection (RTI) within the past 12 months. In the phase 3 trial, patients were aged at least 65 years, did not have COPD, and were not current smokers.

In the phase 2b trial, patients were randomly assigned to using a validated automated randomisation system to oral RTB101 5 mg, RTB101 10 mg once daily, or placebo in part 1 and RTB101 10 mg once daily, RTB101 10 mg twice daily, RTB101 10 mg plus everolimus once daily, or matching placebo in part 2. In the phase 3 trial, patients were randomly assigned to RTB101 10mg once daily or matching placebo. The phase 2b primary outcome was the incidence of laboratory-confirmed RTIs during 16 weeks of winter cold and influenza season and the phase 3 primary outcome was the incidence of clinically symptomatic respiratory illness defined as symptoms consistent with an RTI, irrespective of whether an infection was laboratory-confirmed.

The purpose of our trials was to investigate whether targeting ageing biology with mTOR inhibitors could improve immune function and decrease the incidence of RTIs in older adults at doses that were well tolerated. The mTOR inhibitor RTB101 10 mg once daily for 16 weeks was well tolerated in adults aged at least 65 years, increased expression of IFN-stimulated antiviral genes in peripheral blood, and decreased the incidence of laboratory-confirmed RTIs (the phase 2b primary endpoint), but not the incidence of clinically symptomatic respiratory illness defined as respiratory symptoms consistent with an RTI irrespective of whether an infection was laboratory confirmed (the phase 3 primary endpoint).

Several possible explanations exist for the divergent results of the phase 2b and phase 3 trials, including the change in primary endpoint and changes in the way respiratory symptoms were collected between the two trials. In the phase 2b trial, respiratory illness symptoms were collected during twice weekly telephone calls with patients and the primary endpoint required a set of predefined symptomatic criteria to be met as well as laboratory confirmation of an infection. In the phase 3 trial, respiratory illness symptoms were collected in eDiaries that patients filled out each evening and the primary endpoint was based on symptoms alone without requiring laboratory confirmation of an infection. Multiple investigators in the phase 3 trial anecdotally noted that patients reported in their nightly eDiary respiratory illness symptoms such as cough or headache that were part of the prespecified diagnostic criteria for a clinically symptomatic respiratory illness even when the patient and the investigator did not think that the patient had an RTI.

Despite the negative phase 3 results, important lessons were learned from this clinical development programme that is the largest to date targeting ageing biology in humans. First, the results show that it is possible to target mechanisms underlying ageing biology safely with therapies such as mTOR inhibitors in older adults. Second, the results suggest that therapies that target ageing biology in older adults might ameliorate at least some aspects of ageing organ system dysfunction (such as deficient IFN-induced antiviral responses). Further refinement of clinical endpoints and more precise identification of responder patient populations will be important in future trials of therapies that intervene in ageing biology to improve immune function in older adults.

Reversing age-related alterations of the body is a long-desired goal of humankind. Despite the extravagant premise, the dream of returning to our youth may not be so far-fetched. Nature actually provides an enormous list of molecules, some of which are silenced after birth but could serve as a potential treatment to reverse age, at least at the level of a single yet complicated organ such as the heart. The question remains: can postnatal increase of developmentally relevant proteins and peptides reverse organ ageing or damage in a beneficial way? We believe the answer to this question is yes. In our earlier research, we introduced a naturally secreted small molecule, Thymosin beta-4 (TB4), which is capable of such miracles not only regarding the heart but in the brain and kidneys.

TB4 was first purified from the thymus and binds and alters the cytoskeletal actin filaments by sequestering actin monomers and in doing so, influences actin filament assembly and regulates migration of various cell types such as endothelial cells, myocardial cells, or epicardial progenitors. It equally inhibits cellular death by activating and binding numerous players in the focal adhesion complex, which, eventually, results in the activation of Akt, a proven substrate of ILK with wide-ranging signalling functions that affect growth, survival, and motility. Naturally, all the other mechanisms by which TB4 initiates the increase of cardiac function are still under investigation by a host of scientists worldwide. Undoubtedly, its capability in activating the adult epicardium and its ability to resemble its embryonic function without risking injury suggests grounds for hope that the molecule does achieve the same in other organs.

Reminding adult cells of their highly proliferative state is not without risk, as the applied treatment may easily result in unwanted malignancies. Although TB4 was reported to be a prognostic marker for highly metastatic cancer states and its tumor promo-ting properties were equally demonstrated, its true nature regarding tumorigenesis is controversial. In our hands, the molecule significantly inhibited the progression of pancreatic cancer following systemic administration in mice in vivo. An additional factor supporting this result is that TB4 was equally introduced as a candidate tumor suppressor in male breast cancer and was demonstrated to have a tumor suppressive function in myeloma development by other research teams. In addition, the high safety profile observed in Phase I and Phase II clinical trials this far strongly anticipate that TB4 will be safe and efficacious at the applied local or systemic dose for broad clinical applications in the future.

We still do not know all the details regarding this special molecule; however, we genuinely believe there are more like it concealed in the human body, awaiting discovery. With their help, we may be capable of fulfilling our dream of reversing age.

When an individual is under stress, the undesired effect on the brain often exceeds expectations. Additionally, when stress persists for a long time, it can trigger serious health problems, particularly depression. Recent studies have revealed that depressed patients have a higher rate of brain aging than healthy subjects and that depression increases dementia risk later in life. However, it remains unknown which factors are involved in brain aging triggered by chronic stress. The most critical change during brain aging is the decline in cognitive function. In addition, cellular senescence is a stable state of cell cycle arrest that occurs because of damage and/or stress and is considered a sign of aging.

We used the chronic unpredictable stress (CUS) model to mimic stressful life situations and found that, compared with nonstressed control mice, CUS-treated C57BL/6 mice exhibited depression-like behaviors and cognitive decline. Additionally, the protein expression of the senescence marker p16INK4a was increased in the hippocampus, and senescence-associated β-galactosidase (SA-β-gal)-positive cells were found in the hippocampal dentate gyrus (DG) in CUS-treated mice. Furthermore, the levels of SA-β-gal or p16INK4a were strongly correlated with the severity of memory impairment in CUS-treated mice, whereas clearing senescent cells using the pharmacological senolytic cocktail dasatinib plus quercetin (D + Q) alleviated CUS-induced cognitive deficits.

Our data suggests that targeting senescent cells may be a promising candidate approach to study chronic stress-induced cognitive decline. Our findings open new avenues for stress-related research and provide new insight into the association of chronic stress-induced cellular senescence with cognitive deficits.

Age-related loss of muscle mass and strength is widely attributed to limitation in the capacity of muscle resident satellite cells to perform their myogenic function. This idea contains two notions that have not been comprehensively evaluated by experiment. First, it entails the idea that we damage and lose substantial amounts of muscle in the course of our normal daily activities. Second, it suggests that mechanisms of muscle repair are in some way exhausted, thus limiting muscle regeneration. A third potential option is that the aged environment becomes inimical to the conduct of muscle regeneration.

In the present study, we used our established model of human muscle xenografting to test whether muscle samples taken from cadavers, of a range of ages, maintained their myogenic potential after being transplanted into immunodeficient mice. We find no measurable difference in regeneration across the range of ages investigated up to 78 years of age. Moreover, we report that satellite cells maintained their myogenic capacity even when muscles were grafted 11 days postmortem in our model. We conclude that the loss of muscle mass with increasing age is not attributable to any intrinsic loss of myogenicity and is most likely a reflection of progressive and detrimental changes in the muscle microenvironment such as to disfavor the myogenic function of these cells.

Biomedical technology holds the promise of extending human life spans; however, little research has explored attitudes toward life extension. Investigated attitudes toward life extension about young adults, younger-old adults, and older-old adults. This survey asked young adults (n = 593), younger-old adults (n = 272), and older-old adults (n = 46) whether they would take a hypothetical life extension treatment as well as the youngest and oldest age at which they would wish to live forever.

Age cohorts did not vary in their willingness to use life extension; however, in all three age cohorts, a plurality indicated that they would not use it. Men indicated a higher level of willingness to use the life extension treatment than women. Younger-old and older-old adults indicated that they would prefer to live permanently at an older age than younger adults. If a life extension treatment were to become available that effectively stopped aging, young adults may be likely to use such a treatment to avoid reaching the ages at which older cohorts say they would prefer to live forever.

The difference between an individual's chronological and DNA methylation predicted age (DNAmAge), termed DNAmAge acceleration (DNAmAA), can capture life-long environmental exposures and age-related physiological changes reflected in methylation status. Several studies have linked DNAmAA to morbidity and mortality, yet its relationship with kidney function has not been assessed. We evaluated the associations between seven DNAm aging and lifespan predictors (as well as GrimAge components) and five kidney traits (estimated glomerular filtration rate [eGFR], urine albumin-to-creatinine ratio [uACR], serum urate, microalbuminuria and chronic kidney disease [CKD]) in up to 9688 European, African American and Hispanic/Latino individuals from seven population-based studies.

We identified 23 significant associations in our large trans-ethnic meta-analysis with a consistent direction of effect across studies. Age acceleration measured by the Extrinsic and PhenoAge estimators, as well as the 10-CpG epigenetic mortality risk score (MRS), were associated with all parameters of poor kidney health (lower eGFR, prevalent CKD, higher uACR, microalbuminuria and higher serum urate).

Epigenetic biomarkers which reflect the systemic effects of age-related mechanisms such as immunosenescence, inflammaging, and oxidative stress may have important mechanistic or prognostic roles in kidney disease. Our study highlights new findings linking kidney disease to biological aging, and opportunities warranting future investigation into DNA methylation biomarkers for prognostic or risk stratification in kidney disease.

The idea that sound waves knocking at the skull could boost memory continues to sound far-fetched to many Alzheimer's researchers, but researchers report that scanning ultrasound improved synaptic signaling, increased neurogenesis, and sharpened spatial memory in old wild-type mice. Importantly, this worked without breaching the blood-brain barrier, a commonly used ultrasound trick to provoke a brain response. Whether this technique is appropriate for people remains to be seen, though early stage clinical trials in older adults indicate it may be safe.

Previous work had suggested ultrasound somehow opens TRPA1 calcium channels in astrocytes, which then release glutamate to activate NMDA receptors on nearby neurons. Researchers looked for signs of astrocyte-mediated activation in mouse hippocampal tissue via Western blots, and found that tissue from mice exposed to ultrasound contained more TRPA1 than tissue from control.

Evidence of NMDA activation came when the scientists separated hippocampal tissue into total and postsynaptic fractions. In the postsynaptic fraction, ultrasound had bumped up the amount of NR2B, a subunit of NMDA receptors that is needed for long-term potentiation (LTP), a form of synaptic plasticity. LTP is crucial for learning and memory and by 20 months of age, it has faded. However, the scanning ultrasound had restored LTP in aged mice, as judged by evoked potentials in hippocampal slices. Based on dentate gyrus expression of doublecortin, a marker of new neurons, the authors concluded that ultrasound upped neurogenesis 13-fold. The scientists did not track how long the memory changes lasted. "Because there are changes at the NDMA receptor level, my gut feeling is that ultrasound leads to long-lasting changes."

The COVID-19 pandemic has revealed the pronounced vulnerability of the elderly and chronically-ill to SARS-CoV-2-induced morbidity and mortality. Cellular senescence contributes to inflammation, multiple chronic diseases, and age-related dysfunction, but effects on responses to viral infection are unclear. Here, we demonstrate that senescent cells become hyper-inflammatory in response to pathogen-associated molecular patterns (PAMPs), including SARS-CoV-2 Spike protein-1, increasing expression of viral entry proteins and reducing anti-viral gene expression in non-senescent cells through a paracrine mechanism.

Old mice acutely infected with pathogens that included a SARS-CoV-2-related mouse β-coronavirus experienced increased senescence and inflammation with nearly 100% mortality. Targeting senescent cells using senolytic drugs before or after pathogen exposure significantly reduced mortality, cellular senescence, and inflammatory markers and increased anti-viral antibodies. Thus, reducing the senescent cell burden in diseased or aged individuals should enhance resilience and reduce mortality following viral infection, including SARS-CoV-2.

The re-activation of microglial proliferative programs is the earliest response to pre-pathological events in chronic neurodegenerative diseases, with microglial proliferation increased in Alzheimer's disease (AD). Microglia have a very rapid proliferative response to the incipient accumulation of amyloid-β, during the onset of tau pathology, and in several other related models of neurodegeneration. We and others have demonstrated that the proliferation of microglia is a central contributor to disease progression. The inhibition of microglial proliferation, using CSF1R inhibitors, ameliorates amyloid and tau pathology, and has emerged as a promising target for clinical investigation.

Integrating our knowledge of microglial population dynamics renders an interesting hypothesis. When combined, the cycling events accumulated in microglia from development to disease would put these cells on a trajectory toward cellular senescence. Replicative senescence, the loss of mitotic potential accompanied by significant telomere shortening, occurs once a cell has undergone ∼50 replications, the so-called Hayflick limit. Thus, we hypothesized that the developmental setup of the population, combined with microglial turnover, would pre-condition these cells to undergo replicative senescence when challenged with additional proliferative events (i.e., as a consequence of brain pathology).

Some reports suggest that microglia show telomere shortening and decreased telomerase activity in both aging and end-stage AD. However, to date, no formal evidence has been provided supporting the idea that these progressive changes in the dynamics of microglia are driving the shift of the microglial response from beneficial to detrimental and therefore contributing to the initiation of AD.

Here, we provide evidence that microglia undergo replicative senescence in a model of AD-like pathology and in human AD. We demonstrate that microglia display a senescence-associated profile and that this is dependent on proliferation. Our data support that the early generation of senescent microglia contributes to the subsequent onset and progression of amyloidosis, as well as the associated neuritic damage that is observed in the early stages of AD.

Methuselah Foundation, which co-sponsored the Vascular Tissue Challenge with NASA, today announced the award-winning researchers achieved scientific breakthroughs that promise to dramatically change the future of human health. The first and second place Challenge winners announced by NASA today are the first scientific teams to engineer and sustain thick functioning human tissue in a lab. The Challenge, first conceived by Methuselah Foundation in 2013, was conducted to increase the pace of bioengineering innovations to benefit humans on Earth and future space explorers.

Eleven teams competed in the Challenge to produce an in-vitro, vascularized organ tissue that is more than 1 centimeter thick. Winning tissue had to provide adequate blood flow and survive at least 30 days. The first-place winner was Team Winston from the Wake Forest Institute for Regenerative Medicine, affiliated with Wake Forest School of Medicine. The team, led by Dr. James Yoo, was awarded 300,000. It will also receive 200,000 from CASIS (Center for the Advancement of Science in Space), to fund the cost of conducting a tissue generation experiment in zero gravity.

The second-place winner was Team WFIRM, also from the Wake Forest Institute for Regenerative Medicine. That team, led by Dr. Anthony Atala, was awarded 100,000. Both groups created lab-grown human liver tissues that were robust enough to survive and function like healthy liver tissue found inside our bodies. Winning entries were built using 3D printing technologies. Ongoing progress will ultimately enable physicians to 3D print human organs with a patient's unique DNA.

Protein glycosylation is the biochemical process for which a carbohydrate molecule is covalently attached to a protein functional group. In biology, glycosylation mainly refers to the enzymatic process that binds glycans to proteins, affecting intracellular processes like folding and transport, and playing an important role in many cellular signaling and communication events.

Three major n-glycan structures present in human blood glycoproteins (serum, plasma, and immunoglobulins fraction) have shown clear changes with ageing. Agalactosyl n-linked oligosaccharides (NG0A2F and NG0A2FB) increase with age whereas core-fucosylated biantennary n-glycans (NA2F) decrease with age. A similar trend was observed in a study which aimed to evaluate the effects of the age and gender on the human serum n-glycans profiles: NGA2F and NGA2FB increased gradually with ageing whereas NA2F decreased. Additionally, before the age of 50 years these three glycans changed only slightly with age, but the difference between age groups 41-50 and 51-60 years was statistically significant, indicating that the age-related physiological changes occurred in the fifties.

An ageing biomarker named GlycoAgeTest has been developed, which could possibly forecast disease progression during ageing. This marker is the log of the ratio of two glycans (NGA2F and NA2F), which remains steady up to the age of 40 years and thereafter gradually increases to reach its highest level in nonagenarians. Furthermore, patients with dementia or Cockayne syndrome have shown to have a higher GlycoAgeTest level than age-matched healthy individuals. It was concluded that the value of GlycoAgeTest is better than chronological age for estimating the physiological age of a human individual, and that it could be used as an ageing biomarker for healthy humans.

Glycome analysis is emerging as a source of potential biomarkers in different pathological states. Its analysis is not easy, as the diverse structures of glycans are complex and heterogenic. Moreover, there is a wide range of possible monosaccharide combinations and linkages, that result in structurally complex glycans, which can be attached to proteins, conforming glycosylation post-translational modifications. In clinical studies, the comparison of glycans levels altered in specific diseases often leads to inconsistent results, which cannot be explained completely by the different statistical methods. This may be due to the diversity of the glycome in different populations and even in different environments. Furthermore, the use of a wide range of glycomic methodologies leads to low comparability between studies which hinders the production of clear results.

A novel finding utilizing cellular and zebrafish models has demonstrated how the leakage of mitochondrial dsDNA into the cytosol environment of the cell can contribute to the impairment of brain tissue of patients with Parkinson's disease (PD). "Our results showed for the first time that cytosolic dsDNA of mitochondrial origin leaking and escaping from lysosomal degradation can induce cytotoxicity both in cultured cells, as well as in zebrafish models of Parkinson's disease. This study showed that the leakage of this mitochondrial nucleic material may occur as a result of mitochondrial dysfunction, which may involve genetic mutations in genes encoding mitochondrial proteins or incomplete degradation of mitochondrial dsDNA in the lysosome - which is a 'degradation factory' of the cell. Upon the leakage into the cytoplasm, this undegraded dsDNA is detected by a 'foreign' DNA sensor of the cytoplasm (IFI16) which then triggers the upregulation of mRNAs encoding for inflammatory proteins."

Using a PD zebrafish model (gba mutant), the researchers demonstrated that a combination of PD-like phenotypes including accumulation of cytosol dsDNA deposits, reduced number of dopaminergic neurons after 3 months. Lastly, they further generated a DNase II mutant zebrafish model which exhibited decreased numbers of dopaminergic neurons and demonstrated accumulated cytosolic DNA. Interestingly, when the gba mutant zebrafish was complemented with human DNAse II gene, the overexpression of human DNAse II decreased cytosolic dsDNA deposits, rescued neuro-degradation by rescuing the number of dopaminergic and noradrenergic neurons after 3 months. This demonstrated that neurodegenerative phenotype of gba mutant zebrafish induced by dsDNA deposits in the cytosol can be restored by DNAse II.

In a step further, to determine the effect of cytosolic dsDNA of mitochondrial origin in human brain with PD, researchers inspected postmortem human brain tissues from patients who were diagnosed with idiopathic PD. They observed abundance of cytosolic dsDNA of mitochondrial origin in medulla oblongata of postmortem brain tissues, the levels of IFI16 were also markedly increased in these brain tissues.

Mesenchymal stem cells (MSCs) are multipotent progenitor cells that can be isolated from the bone marrow, adipose tissue, dental tissues, skin, salivary gland, limb buds, menstrual blood, and perinatal tissues. Although MSCs do not differentiate into immune cells, MSCs provide a supporting microenvironmental niche for hematopoietic stem cells (HSCs) to differentiate into myeloid and lymphoid cells, which are essentially the immune cells. One of the speculated theories of declining immunity as the host ages is the MSC senescence. Subsequently, the functions and structures of MSCs, which are significant in maintaining the immune system, diminishes.

Numerous studies have proven that MSCs have low immunogenicity, excellent immunomodulatory function, and homing capability to regenerate damaged tissues through multipotent differentiation and paracrine secretion. Despite that, current studies are not primarily focused on aging or the restoration of the immune system. There have been extensive studies conducted on pathological conditions than actual aging itself. Aging and MSC were studied separately, but the similarities of the immune markers involved may come into convergence. The proliferative capacity and immunomodulatory function of MSCs could aid in the restoration of the immune cells and reduce the pro-inflammatory markers since these parameters are observed in aging as well. MSCs might not be a permanent solution to restore a healthy cell population, however. MSCs may have been seen as effective in past studies due to their paracrine effects but not cell replacement. This may explain the relatively fast drop in the inflammatory state when MSC therapy commences.

Some evidence shows that the ameliorating effects of MSCs on the immune system are not due to direct engraftment and cell replacement, but rather paracrine manner and direct cell-to-cell contact. MSCs secrete soluble paracrine factors and express IL-10, which is an anti-inflammatory and immunoregulatory cytokine. Furthermore, they produce IL-6 and IL-8, which are known to be associated with MSC tissue repair potential. Subsequently, MSCs control the inflammatory state as evidence of the reduced expression of proinflammatory cytokines such as TNF-α, IL-1β, IL-6, and CRP. Moreover, MSC-secreted TGF-β has a role in macrophage polarization towards the M2 phenotype. These M2 macrophages stimulate the expression of IL-10, which alleviates inflammation. The mechanism of action of MSCs on the immune system is not constitutively inhibitory, but is acquired after exposure to the inflammatory environment with IFN-γ. IFN-γ is one of the cytokines released by T cytotoxic cells during inflammation. Therefore, in Th17 centered inflammatory response, MSC treatment would require the addition of regulatory T cells to successfully regulate the inflammation.

Immunosenescence is an inevitable phenomenon that involves the remodeling of the immune system with age. This complex interaction between the age-accumulated insults, aged HSCs bias to myeloid cells, and both the innate and adaptive immune system results in a chronic, subclinical systemic inflammation termed as 'inflammaging'. The individuals over 65 years old have increased risk of infection, cancer, higher morbidity, and mortality of disease, and reduced vaccine efficacy. Currently, there are no effective countermeasures available to ameliorate immunosenescence. MSC therapy is a promising modality to rejuvenate the aged immune system. As of now, studies have shown that MSCs can safely reduce the inflammatory markers, restore the T cell repertoire, and improve the histopathology of inflammatory disease.