Rejuvenation research最新文献

The development of senomorphic drugs to attenuate the senescent phenotype and senolytics to clear pro-inflammatory senescent cells (SCs) to treat aging-associated disorders is being hotly pursued. The effort is complicated by the fact that SCs play a constructive role in some cellular processes such as tissue repair and wound healing. However, concerns about efficacy, which SCs to target, and unwanted side effects have created potential roadblocks. Chimeric antigen receptor T cells directed against urokinase-type plasminogen activator receptor, which is expressed on at least a subset of SCs in atherosclerotic plaques and fibrotic livers, removed SC and improved glucose metabolism. A vaccine targeting CD153-expressing senescent T cells also improved glucose metabolism in obese mice. Recent work to selectively target SCs associated with several pathologies has resulted in the creation of a peptide vaccine that primarily targets endothelial cells expressing high levels of GPNMB, recently identified as a biomarker of senescence. The vaccine reduces atherosclerotic plaque burden and metabolic dysfunction such as glucose intolerance in mouse models of obesity and atherosclerosis. For translation to humans the activity of the vaccine will need to be tightly controlled, as the target GPNMB has multiple roles in normal physiology, including acting to inhibit and possibly resolve inflammation. A promising alternative approach would be to use passive immunization with a monoclonal antibody directed against GPNMB.

Alzheimer's disease (AD) has no cure, mainly because of late diagnosis. Early diagnostic biomarkers are crucial. Phospholipases A₂ (PLA₂) are hydrolases with several functions in the brain, nevertheless their deregulation contributes to neurodegeneration. We evaluated platelet total PLA₂ activity (p_totPLA₂) in healthy elderly subjects (HE, n = 102), patients suffering from mild cognitive impairment (MCI, n = 90) and AD (n = 91). Platelets are considered "circulating neurons" and p_totPLA₂ appears to mirror the cerebral activity. p_totPLA₂ of the three cohorts was similar, but in MCI the higher p_totPLA₂ the worse the global cognitive status (Mini Mental State Examination score [MMSE]) and in AD the lower p_totPLA₂ the more severe the pathology stage (Clinical Dementia Rating [CDR]). Accordingly, MCI with MMSE ≥26 overlapped HE, in MCI with MMSE <26 and in AD with CDR 1 p_totPLA₂ increased, in AD with CDR 2 p_totPLA₂ decreased. In MCI p_totPLA₂ positively correlated with blood oxidation and inflammation, in AD it was the opposite. Finally, Discrimination Index (DI)-calculated multiplying p_totPLA₂, oxidative level and Cu/Zn ratio (an inflammation parameter)-differentiated MCI patients who progressed to dementia in the following 24 months and AD patients with the worse pathology development. Summarizing, p_totPLA₂ changes during MCI and AD progression, is linked, in opposite way, to oxidative/inflammatory status in MCI and AD and might help, when included in DI, to identify MCI converters to dementia and AD patients with the more severe prognosis. p_totPLA₂ may have a diagnostic/prognostic value and be a potential therapeutic target.

The telomere length (TL) has increasingly been used as a biomarker of human aging because it has been shown to predict the chances of survival and longevity. Oxidative stress is presumed to be a major cause of telomere shortening, but the importance of oxidative stress as a determinant of telomere shortening remains less clear and has recently been questioned. We analyzed 105 healthy subjects of both sexes between the ages of 20-77 years. The TL and biomarkers of oxidative stress were estimated as per standard protocols. A significant (p < 0.001) age-dependent decline in TL was observed. TL was positively correlated with the ferric reducing ability of plasma value (r = 0.8811) and reduced glutathione (r = 0.8209), whereas negatively correlated with malondialdehyde (r = -0.7191). Our findings supported the idea of a possible correlation between the TL and biomarkers of oxidative stress in aging. The study has remarkable scope in medical science as the findings on correlation of TL with biomarkers of oxidative stress in aging are novel and they will help in further research against oxidative stress.

Mesenchymal stromal cells from adipose tissue (adipose stromal cells, ASCs) are regulators of repair processes in situ by paracrine mechanisms. These unique capabilities make ASCs candidates for the regenerative medicine applications, including cell-assisted lipotransfer method. ASC aging processes have been extensively researched in vitro, there is however limited information about the impact of ASC aging on their biological role in tissue regeneration in vivo. The aim of our study was the research of the possible effects of aging processes of ASCs resulting from the donor age or from in vitro aging during long-term culture (ASC expansion in bioreactors) on their capability to support survival of adipose subcutaneous transplants in rats. The supportive in vivo effects of ASCs from young donors were compared with the effects of ASCs from old donors and ASCs "aged" in long-term in vitro cultures. Fat grafts enriched with ASCs (regardless of their age) retain their volume longer than fat grafts without ASCs supplementation. Vascular expansion in cell-enriched fat grafts was more intense when compared with the controls. It may be concluded that the aging of ASCs does not substantially reduce their ability for the support of the survival of adipose tissue grafts.

Stem cell dysfunction is a hallmark of aging. Much recent study suggests that epigenetic changes play a critical role in the loss of stem cell function with age. However, the underlying mechanisms require elucidation. A recent report describes a process by which mild mitochondrial stress associated with aging causes lysosomal-mediated decreases in CiC, the mitochondrial citrate transporter, in bone marrow-derived mesenchymal stem cells (MSCs). This, in turn, results in a deficit of acetyl-CoA in the nucleus and hypoacetylation of histones. The altered epigenome results in skewered stem cell differentiation favoring adipogenesis and disfavoring osteogenesis, which is problematic given the role the MSCs play in maintaining the integrity of bone tissue. Restoration of nuclear acetyl-CoA by either ectopic expression of CiC or acetate supplementation of MSCs in culture rejuvenates the MSC, restoring the potential to efficiently differentiate along the osteogenic lineage. Citrate, which has recently been reported to extend lifespan in Drosophila, chemically incorporates acetyl-CoA and may prove useful to restore cytoplasmic and nuclear acetyl-CoA levels. The general applicability of the CiC defect in old cells, particularly stem cells, should be established.

Theses reviewed in this issue include "A Rapid Lipid-Based Approach for Normalization of Quantum Dot-Detected Biomarker Expression on Extracellular Vesicles in Complex Biological Samples," "Cancer Dynamics Under a Chemotherapeutic Stress Gradient Using a Microfluidic In Vitro Tumor Environment," "Cells Exhibiting Strong P16ink4a Promoter Activation In Vivo Display Features of Senescence," "HLA-G Dimer Prolongs Kidney Allograft Survival by Inhibiting CD8⁺ T Cell Activation and Granzyme B Expression," "Lysophosphatidic Acid Suppression of CD8 T Cell Signaling and Function," and "Targeting Therapeutic T Cells to the Bone Marrow Niche."

External skin-stretching devices have been developed and used for wound closure since 1970s. Devices such as Miami STAR^®, SureClosure^®, TopClosure^®, and WiseBand^® have their own advantages and disadvantages. The modified external skin-stretching technique of this case series study has the advantage to improve tension distribution and simplified the application. Between January 2014 and June 2017, 20 patients were treated with the modified external skin-stretching device for the closure of the skin defects of the trunk (n = 6) and extremities (n = 14). Skin defects ranged from 8 × 5 to 19 × 16 cm achieved primary closure with the utilization of the modified skin-stretching device without major complications. Subsequent minor revisions were performed under local anesthesia between 6 and 12 months postoperatively. The modified skin-stretching device utilized biomechanical properties and mechanical creep of skin tissue to achieve a reliable and effective primary closure for moderate to extensive skin defects. Therefore, this modified external skin-stretching technique provided, in the appropriate setting, an effective alternative to skin grafts or free flaps.

A major limitation in aging research is the lack of reliable biomarkers to assess phenotypic changes with age or monitor response to antiaging interventions. This study investigates the role of intracellular ferrous iron (Fe₂⁺) as a potential biomarker of senescence. Iron is known to accumulate in various tissues with age and recent studies have demonstrated that its level increases dramatically in senescent cells. The current techniques used to measure the accumulation of iron are cumbersome and only measure total iron not specific isotopes such as the redox reactive Fe₂⁺. It is still to be determined whether the damaging form of iron (Fe₂⁺) is specifically elevated in senescent cells. In this study, we assessed the potential use of a newly discovered Fe₂⁺ reactive probe (SiRhoNox-1) for selective labeling of senescent cells in vitro. For this we have generated various senescent cell models and subjected them to SiRhoNox-1 labeling. Our results indicate that SiRhoNox-1 selectivity labels live senescent cells and was more specific and faster than current staining such as SA-βGal or a derived fluorescent probe C₁₂FDG. Together these findings suggest that SiRhoNox-1 may serve as a convenient tool to detect senescent cells based on their ferrous iron level.