Decline In Cellular Function Research Articles

Advancing Longevity: Exploring Antiaging Pharmaceuticals in Contemporary Clinical Trials Amid Aging Dynamics.

Aging is an inevitable biological process that significantly impacts human health, leading to a decline in cellular function and an increase in cellular damage. This study elucidates the burgeoning potential of antiaging pharmaceuticals in mitigating the thriving burden of chronic conditions linked to advancing age. It underscores the pivotal role of these pharmacotherapeutic agents in fostering longevity free from debilitating age-related afflictions, notably cardiovascular disorders, neoplastic processes, and neurodegenerative pathologies. While commendable strides have been made evident in preclinical models, it is crucial to thoroughly investigate their effectiveness and safety in human groups. In addition, ethical concerns about fair access, societal impacts, and careful resource distribution are significant in discussions about developing and using antiaging medications. By approaching the development and utilization of antiaging medications with diligence and foresight, we can strive toward a future where individuals can enjoy extended lifespans free from the debilitating effects of age-related ailments.

Full-length direct RNA sequencing reveals extensive remodeling of RNA expression, processing and modification in aging Caenorhabditis elegans.

Organismal aging is marked by decline in cellular function and anatomy, ultimately resulting in death. To inform our understanding of the mechanisms underlying this degeneration, we performed standard RNA sequencing and Nanopore direct RNA sequencing over an adult time course in Caenorhabditis elegans. Long reads allowed for identification of hundreds of novel isoforms and age-associated differential isoform accumulation, resulting from alternative splicing and terminal exon choice. Genome-wide analysis reveals a decline in RNA processing fidelity and a rise in inosine and pseudouridine editing events in transcripts from older animals. In this first map of pseudouridine modifications for C. elegans, we find that they largely reside in coding sequences and that the number of genes with this modification increases with age. Collectively, this analysis discovers transcriptomic signatures associated with age and is a valuable resource to understand the many processes that dictate altered gene expression patterns and post-transcriptional regulation in aging.

Longevity and anti-aging effects of curcumin supplementation.

Aging is a gradual and irreversible process that is accompanied by an overall decline in cellular function and a significant increase in the risk of age-associated disorders. Generally, delaying aging is a more effective method than treating diseases associated with aging. Currently, researchers are focused on natural compounds and their therapeutic and health benefits. Curcumin is the main active substance that is present in turmeric, a spice that is made up of the roots and rhizomes of the Curcuma longa plant. Curcumin demonstrated a positive impact on slowing down the aging process by postponing age-related changes. This compound may have anti-aging properties by changing levels of proteins involved in the aging process, such as sirtuins and AMPK, and inhibiting pro-aging proteins, such as NF-κB and mTOR. In clinical research, this herbal compound has been extensively examined in terms of safety, efficacy, and pharmacokinetics. There are numerous effects of curcumin on mechanisms related to aging and human diseases, so we discuss many of them in detail in this review.

Humanin and Its Pathophysiological Roles in Aging: A Systematic Review.

Senescence is a cellular aging process in all multicellular organisms. It is characterized by a decline in cellular functions and proliferation, resulting in increased cellular damage and death. These conditions play an essential role in aging and significantly contribute to the development of age-related complications. Humanin is a mitochondrial-derived peptide (MDP), encoded by mitochondrial DNA, playing a cytoprotective role to preserve mitochondrial function and cell viability under stressful and senescence conditions. For these reasons, humanin can be exploited in strategies aiming to counteract several processes involved in aging, including cardiovascular disease, neurodegeneration, and cancer. Relevance of these conditions to aging and disease: Senescence appears to be involved in the decay in organ and tissue function, it has also been related to the development of age-related diseases, such as cardiovascular conditions, cancer, and diabetes. In particular, senescent cells produce inflammatory cytokines and other pro-inflammatory molecules that can participate to the development of such diseases. Humanin, on the other hand, seems to contrast the development of such conditions, and it is also known to play a role in these diseases by promoting the death of damaged or malfunctioning cells and contributing to the inflammation often associated with them. Both senescence and humanin-related mechanisms are complex processes that have not been fully clarified yet. Further research is needed to thoroughly understand the role of such processes in aging and disease and identify potential interventions to target them in order to prevent or treat age-related conditions. This systematic review aims to assess the potential mechanisms underlying the link connecting senescence, humanin, aging, and disease.

Integrated metabolomics and phosphoproteomics reveal the protective role of exosomes from human umbilical cord mesenchymal stem cells in naturally aging mouse livers

BackgroundAging is characterized by a general decline in cellular function, which ultimately affects whole body homeostasis. This study aimed to investigate the effects and underlying mechanisms of exosomes derived from human umbilical cord mesenchymal stem cells (hUCMSC-exos) on the livers of naturally aging mice. MethodTwenty-two-month-old C57BL6 mice were used as a natural aging animal model, divided into a saline-treated wild‐type aged control group (WT-AC) and a hUCMSC-exo-treated group (WT-AEX), and then detected by morphology, metabolomics and phosphoproteomics. ResultsMorphological analysis showed that hUCMSC-exos ameliorated structural disorder and decreased markers of senescence and genome instability in aging livers. Metabolomics showed that hUCMSC-exos decreased the contents of saturated glycerophospholipids, palmitoyl-glycerols and eicosanoid derivatives associated with lipotoxicity and inflammation, consistent with the decreased phosphorylation of metabolic enzymes, such as propionate-CoA ligase (Acss2), at S267 detected by phosphoproteomics. Moreover, phosphoproteomics indicated that hUCMSC-exos reduced the phosphorylation of proteins participating in nuclear transport and cancer signaling, such as heat shock protein HSP90-beta (Hsp90ab1) at S226 and nucleoprotein TPR (Tpr) at S453 and S379, while increasing those involved in intracellular communication, such as calnexin (Canx) at S563 and PDZ domain-containing protein 8 (Pdzd8). Finally, phosphorylated HSP90β and Tpr were verified predominantly in hepatocytes. ConclusionHUCMSC-exos improved metabolic reprogramming and genome stability mainly associated with phosphorylated HSP90β in hepatocytes in natural aging livers. This work provides a comprehensive resource of biological data by omics to support future investigations of hUCMSC-exos in aging.

Aging and cancer hallmarks as therapeutic targets

The prevalence of age-related diseases has been progressively increasing worldwide. The pathogenesis of these disorders, including cancer, is closely associated with an age-dependent decline in cellular functions. There are multiple layers of crosstalk between aging processes and oncogenesis. Therefore, a better understanding of the interplay between aging and cancer will facilitate the development of novel therapeutic intervention strategies for malignancies at advanced ages. Recent review articles have concisely summarized and updated aging and cancer hallmark features and adequately discussed the interplays at both the cellular and molecular levels. Because aging and cancer share several key mechanisms that define the hallmarks, targeting shared features, such as cellular senescence, may be beneficial for cancer prevention and treatments. Notably, senolysis, an innovative therapeutic intervention for selectively removing senescent cells, holds great promise for developing new therapeutic approaches for cancers and other age-related diseases, such as viral infections and cardiovascular diseases. Herein we briefly summarize the recently updated knowledge on aging and cancer hallmarks, as well as the advances in senolysis for age-related conditions.

Pilot study evaluating the therapeutic effects of a new pre-mixed injectable product of low molecular weight (LMW) hyaluronic acid added to six amino acids (HY6AA +Formula) in facial skin aging

Introduction: Skin aging is a complex biological phenomenon, it is the result of an intrinsic decline in cellular functions due to age and genetically programmed, added to a continuous exposure of various harmful external factors that influence its trend. Both mechanisms modify the structure of the extracellular matrix (ECM) by acting on the quantity and composition of its proteins: type III collagen constitutes 50% of the collagen in the dermis of the neonatal skin but only 5% of the collagen in the aging adult skin, type IV collagen, an important component of the basement membrane, forms anchor plates between types of structural collagen, it decreases with age after 35 years affecting the thickness of the epithelial basement membrane significantly. Aims of the study: The Aim of the study was to evaluate the therapeutic effects of a new pre-mixed injectable product of not cross-linked LMW Hyaluronic Acid (50-250 KDaltons) added to a specific mixture of six amino acids ( HY6AA + Formula) to improve the signs of chrono and photo-aging of the skin of the facial area, through a simple and minimally invasive injectable procedure with fast obtaining results. Materials and methods: The open clinical pilot trial was conducted by two centres under medical control. 3,5 ml HY6AA+Formula was performed by injecting 3 times at intervals of 2 weeks each. The Visia device as well as the GAIS (Global Aesthetic Improvement Scale) and VAS scale, the skin elasticity scale and the wrinkle correction scale were used for the assessment. Efficacy evaluations were performed previously to each injection treatment, performed every two week for three times, and 4 weeks after the third injection. Skin elasticity was evaluated by Pinching Test immediately after each treatment and at 4 weeks after the third injection. Conclusions: The photo analysis by Visia device proves the significant effectiveness of HY6AA + Formula. The data recorded on the skin texture improvement, dyschromia and skin elasticity are very encouraging, especially considering the minimal invasiveness of the procedure and the limited number of sessions required. The improvement of skin quality in most cases occur after the first treatment, and as the treatment protocol progresses, patients' feelings and their individual assessment of skin quality also gradually improve.

A biomimetic shock model on the effect of endothelial aging on vascular barrier properties.

Aging is characterized by a decline in cellular function, which has an adverse effect on the biologic response to injury. Both aging and trauma/hemorrhagic shock (T/HS) increase oxidative stress which impairs the vascular endothelium (EC) and glycocalyx (EG). The additive effect of aging on EC and EG damage following T/HS are unknown. This was studied in an in vitro model. Confluent endothelial cell monolayers from primary aortic endothelial cells from 10-week-old mice ("young" cells) or primary aortic cells from 65-week-old mice ("aged" cells) were established in microfluidic devices (MFDs) and perfused at constant shear conditions overnight. Mouse endothelial cell monolayers were then exposed to hypoxia/reoxygenation alone and/or epinephrine or norepinephrine. Endothelial glycocalyx degradation was indexed as well as subsequent endothelial injury/activation. Aged endothelial cells showed increase glycocalyx shedding and subsequent loss of glycocalyx thickness. This lead to a more pronounced level of EC injury/activation compared with young endothelial cells. Although exposure to biomimetic shock conditions exacerbated both endothelial glycocalyx shedding and endothelial injury in both aged and young endothelial cells, the effect was significantly more pronounced in aged cells. Advanced age is associated with worse outcomes in severely injured trauma patients. Our study demonstrates that there is increased EG shedding and a diminished EG layer in aged compared to "young" endothelial cell layers. Biomimetic shock conditions lead to an even greater impairment of the endothelial glycocalyx in aged versus young endothelial cell monolayers. It appears that these effects are a consequence of aging related oxidative stress at both baseline and shock conditions. This exacerbates shock-induced endotheliopathy and may contribute to untoward effects on patient outcomes in this population.

Cellular Senescence Affects Cardiac Regeneration and Repair in Ischemic Heart Disease.

Ischemic heart disease (IHD) is defined as a syndrome of ischemic cardiomyopathy. Myogenesis and angiogenesis in the ischemic myocardium are important for cardiomyocyte (CM) survival, improving cardiac function and decreasing the progression of heart failure after IHD. Cellular senescence is a state of permanent irreversible cell cycle arrest caused by stress that results in a decline in cellular functions, such as proliferation, migration, homing, and differentiation. In addition, senescent cells produce the senescence-associated secretory phenotype (SASP), which affects the tissue microenvironment and surrounding cells by secreting proinflammatory cytokines, chemokines, growth factors, and extracellular matrix degradation proteins. The accumulation of cardiovascular-related senescent cells, including vascular endothelial cells (VECs), vascular smooth muscle cells (VSMCs), CMs and progenitor cells, is an important risk factor of cardiovascular diseases, such as vascular aging, atherosclerotic plaque formation, myocardial infarction (MI) and ventricular remodeling. This review summarizes the processes of angiogenesis, myogenesis and cellular senescence after IHD. In addition, this review focuses on the relationship between cellular senescence and cardiovascular disease and the mechanism of cellular senescence. Finally, we discuss a potential therapeutic strategy for MI targeting senescent cells.

Traumatic oral mucosal lesions in elderly dental patients - An institutional study

Oral trauma in elderly population constitutes an increasingly recognized problem. Aging results in a progressive decline in cellular function, which leads to loss of their capacity to respond to an injury. The aim of the study is to check the prevalence of traumatic oral mucosal lesions in elderly population/patients visiting a dental clinic. Elderly patients with oral mucosal lesions reported to dental hospitals were selected. Data from 86000 patients visiting Saveetha Dental College during the time period of June 2019 to March 2020 were reviewed, and the data was collected. This is a single centred retrospective study conducted in a private dental institution, Chennai. The collected data were tabulated and analysed using SPSS software by IBM. Out of 80 patients, 56.3% of the patients were of age 60 to 65 years. 42% of the patients had Denture stomatitis which was the highest among all the traumatic oral mucosal lesions. Males were more prevalent to oral mucosal lesions with 57.5% than females. The most common site with oral mucosal lesions is palate with 44%. The overall prevalence of traumatic oral mucosal lesions in the elderly population is high. Denture stomatitis is the most commonly occurring oral traumatic mucosal lesion among elderly patients visiting the dental clinic.

Age-Related Dysfunctions: Evidence and Relationship with Some Risk Factors and Protective Drugs.

The theories interpreting senescence as a phenomenon favored by natural selection require the existence of specific, genetically determined and regulated mechanisms that cause a progressive age-related increase in mortality. The mechanisms defined in the subtelomere-telomere theory suggest that progressive slackening of cell turnover and decline in cellular functions are determined by the subtelomere-telomere-telomerase system, which causes a progressive "atrophic syndrome" in all organs and tissues. If the mechanisms underlying aging-related dysfunctions are similar and having the same origin, it could be hypothesized that equal interventions could produce similar effects. This article reviews the consequences of some factors (diabetes, obesity/dyslipidemia, hypertension, smoking, moderate use and abuse of alcohol) and classes of drugs [statins, angiotensin-converting enzyme (ACE) inhibitors, sartans] in accelerating and anticipating or in counteracting the process of aging. The evidence is compatible with the programmed aging paradigm and the mechanisms defined by the subtelomere-telomere theory but it has no obvious discriminating value against the theories of non-programmed aging paradigm. However, the existence of mechanisms, determined by the subtelomere-telomere-telomerase system and causing a progressive age-related decline in fitness through gradual cell senescence and cell senescence, is not justifiable without an evolutionary motivation. Their existence is expected by the programmed aging paradigm, while is incompatible with the opposite paradigm.

PROLONGATION OF HUMAN LIFESPAN BY IMMATURE PEAR EXTRACT MEDIATED SIRTUIN-RELATED GENE EXPRESSION

Demographics of the world are changing rapidly with older populations growing at an unprecedented rate. Cellular senescence, a decline of cellular function due to aging, causes gradual loss of physiological functions. Several cellular senescence-related chronic diseases, such as metabolic syndrome, cardiovascular disease, cancer, osteoporosis, diabetes, and hypertension, negatively affect the quality of human life. Intervention in the cellular senescence process may reduce these incidences and slow the progression of age-related diseases, while contributing to the longevity of healthy human lifespans. Saccharomyces cerevisiae, the budding yeast, is a simple model system that can provide significant insights into the human genetics and molecular biology of senescence and is considered suitable as a cellular model for research on mammalian cells. The aim of our study was to investigate the anti-aging effects of immature pear fruit extract (IPE) on yeast cells and its possible application to extend healthy lifespan in humans. Anti-aging effects of IPE were investigated using a chronological lifespan assay on S. cerevisiae cells. The chronological lifespan of the yeast treated with IPE at 1% (v/v) was significantly extended than that of untreated cells (p < 0.05). The expression of sirtuin-related genes, which regulate cellular senescence, was examined by reverse transcription-polymerase chain reaction and found to be significantly increased following IPE treatment. These results suggest that sirtuin-related genes have important roles in IPE-regulated lifespan extension, which provides a mechanism by which IPE could affect mammalian cells and potentially extend healthy human lifespans.

Proteome Oxidative Modifications and Impairment of Specific Metabolic Pathways During Cellular Senescence and Aging.

Accumulation of oxidatively modified proteins is a hallmark of organismal aging in vivo and of cellular replicative senescence in vitro. Failure of protein maintenance is a major contributor to the age-associated accumulation of damaged proteins that is believed to participate to the age-related decline in cellular function. In this context, quantitative proteomics approaches, including 2-D gel electrophoresis (2-DE)-based methods, represent powerful tools for monitoring the extent of protein oxidative modifications at the proteome level and for identifying the targeted proteins, also referred as to the "oxi-proteome." Previous studies have identified proteins targeted by oxidative modifications during replicative senescence of human WI-38 fibroblasts and myoblasts and have been shown to represent a restricted set within the total cellular proteome that fall in key functional categories, such as energy metabolism, protein quality control, and cellular morphology. To provide mechanistic support into the role of oxidized proteins in the development of the senescent phenotype, untargeted metabolomic profiling is also performed for young and senescent myoblasts and fibroblasts. Metabolomic profiling is indicative of energy metabolism impairment in both senescent myoblasts and fibroblasts, suggesting a link between oxidative protein modifications and the altered cellular metabolism associated with the senescent phenotype of human myoblasts and fibroblasts.

Effects of sulforaphane on D-galactose-induced liver aging in rats: Role of keap-1/nrf-2 pathway.

Aging; a biological phenomenon characterized by progressive decline in cellular functions, is considered as a major risk factor of various liver diseases that plays as an adverse prognostic role, thus increasing mortality rate. However, diet is the main environmental factor that has a major impact on the aging process whereas; sulforaphane (SFN), an isothiocyanate organosulfur compound in cruciferous vegetables, has been reported with myriad biological effects. In the present study, SFN antiaging properties were evaluated on D-galactose (D-Gal)-induced liver aging in rats. For this purpose, forty adult male Wistar rats were divided into five groups. All animals, except the normal control, were intraperitoneally injected with D-Gal (300 mg/kg/day for 5 days a week) for six consecutive weeks. In the hepatoprotective groups, animals received oral SFN (0.5, 1.0 and 2.0 mg/kg) for 6 weeks concurrently with D-GAL. SFN administration improved liver biomarkers through decreasing serum levels of AST, ALT, total and direct bilirubin when compared to D-Gal-aging group. SFN significantly increased hepatic GSH level as well as catalase and glutathione-S-transferase activities while counteracted the elevation in hepatic oxidative stress markers; MDA, NO and protein carbonyl in aged rats. SFN abrogated the dysregulation in hepatic Keap-1, Nrf-2 and HO-1and limited the elevation of TNF-α and TGF-β concentrations in aging liver. Histopathologically, SFN decreased the intensity of hepatic fibrous proliferation in D-Gal-induced aging. In conclusion, SFN has shown hepatic anti-aging potential through promoting the antioxidant machinery via regulating Keap-1, Nrf-2 and HO-1 and antioxidant enzyme activities as well as ameliorating oxidative stress, hampering the inflammatory cytokines; TNF-ɑ and TGF-β, and limiting hepatic fibrosis in a dose dependent manner.

Late‐In‐Life Treadmill‐Training Ameliorates the Decline in Cardiac Autophagy Associated with Aging in Mice

Protein aggregates accumulate and organelles become damaged and/or dysfunctional during the process of aging. A progressive loss of the cellular quality control mechanism autophagy contributes to this age‐associated decline in cellular function in many organs. Evidence for an age‐associated repression in cardiac autophagy is not consistent. We hypothesized that 24‐month old (old) male C57Bl6/J mice exhibit repressed autophagosome formation in the heart, myocardial dysfunction, and reduced exercise capacity vs. 6‐month old (adult) mice. First, cardiac lysates from old mice displayed reduced (p&lt;0.05) accumulation of LC3II/GAPDH and degradation of p62 vs. adult animals (n=12 per group). Second, the lysosomal acidification inhibitor chloroquine (CQ) induced accrual (p&lt;0.05) of LC3II/GAPDH and p62 in hearts from adult but not old mice (n=7 per group). Third, left ventricular mass was greater (p&lt;0.05), and indices of systolic, diastolic, and global left ventricular function (transthoracic echocardiography) were impaired, in old vs. adult animals (n=12 per group). Finally, maximal workload performed during a treadmill‐test was less (p&lt;0.05) in aged (n=11) vs. adult (n=12) mice. To determine whether late‐in‐life exercise training induces cardiac autophagy, separate cohorts of male mice completed a progressive‐resistance treadmill‐running program (old‐ETR) or remained sedentary (old‐SED) from 21–24 months. Body composition, exercise performance during a maximal workload test, soleus muscle citrate synthase (CS) activity, indices of cardiac antioxidant enzyme activity, markers of cardiac autophagy, and indices of myocardial function, all improved (p&lt;0.05) in old‐ETR (n=11) vs. old‐SED (n=12) mice. These data are the first to demonstrate that markers of cardiac autophagy are elevated, and indices of myocardial function are improved, in old mice that complete a treadmill‐training regimen that is sufficient to increase skeletal muscle CS activity and maximal exercise capacity. These data provide strong proof of concept to evaluate cause and effect relationships among exercise‐training, myocardial.Support or Funding InformationUU Research Fellowship (JMC); APS UGRF (CR); AHA17POST33670663 (SKP); NIHRO1DK098646‐01A1, NIHRO1DK099110, AHA16GRANT30990018 (SB); AHA16GRNT31050004, NIH RO3AGO52848, NIH RO1HL141540 (JDS).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Enhanced inter-compartmental Ca2+ flux modulates mitochondrial metabolism and apoptotic threshold during aging

BackgroundSenescence is characterized by a gradual decline in cellular functions, including changes in energy homeostasis and decreased proliferation activity. As cellular power plants, contributors to signal transduction, sources of reactive oxygen species (ROS) and executors of programmed cell death, mitochondria are in a unique position to affect aging-associated processes of cellular decline. Notably, metabolic activation of mitochondria is tightly linked to Ca2+ due to the Ca2+ -dependency of several enzymes in the Krebs cycle, however, overload of mitochondria with Ca2+ triggers cell death pathways. Consequently, a machinery of proteins tightly controls mitochondrial Ca2+ homeostasis as well as the exchange of Ca2+ between the different cellular compartments, including Ca2+ flux between mitochondria and the endoplasmic reticulum (ER). MethodsIn this study, we investigated age-related changes in mitochondrial Ca2+ homeostasis, mitochondrial-ER linkage and the activity of the main ROS production site, the mitochondrial respiration chain, in an in vitro aging model based on porcine aortic endothelial cells (PAECs), using high-resolution live cell imaging, proteomics and various molecular biological methods. ResultsWe describe that in aged endothelial cells, increased ER-mitochondrial Ca2+ crosstalk occurs due to enhanced ER-mitochondrial tethering. The close functional inter-organelle linkage increases mitochondrial Ca2+ uptake and thereby the activity of the mitochondrial respiration, but also makes senescent cells more vulnerable to mitochondrial Ca2+-overload-induced cell death. Moreover, we identified the senolytic properties of the polyphenol resveratrol, triggering cell death via mitochondrial Ca2+ overload exclusively in senescent cells. ConclusionBy unveiling aging-related changes in the inter-organelle tethering and Ca2+ communications we have advanced the understanding of endothelial aging and highlighted a potential basis to develop drugs specifically targeting senescent cells.

The Eye, Oxidative Damage and Polyunsaturated Fatty Acids.

Polyunsaturated fatty acids (PUFA) are known to have numerous beneficial effects, owing to their anti-inflammatory and antioxidant properties. From a metabolic standpoint, the mitochondria play a fundamental role in cellular homeostasis, and oxidative stress can affect their functioning. Indeed, the mitochondria are the main source of ROS, and an imbalance between ROS and antioxidant defenses leads to oxidative stress. In addition, aging, the decline of cellular functions, and continual exposure to light underlie many diseases, particularly those of the eye. Long-term exposure to insults, such as UV light, visible light, ionizing radiation, chemotherapeutics, and environmental toxins, contribute to oxidative damage in ocular tissues and expose the aging eye to considerable risk of pathological consequences of oxidative stress. Ample antioxidant defenses responsible for scavenging free radicals are essential for redox homeostasis in the eye, indeed, eye tissues, starting from the tear film, which normally are exposed to high oxygen levels, have strong antioxidant defenses that are efficient for protecting against ROS-related injuries. On the contrary, instead, the trabecular meshwork is not directly exposed to light and its endothelial cells are poorly equipped with antioxidant defenses. All this makes the eye a target organ of oxidative damage. This review focuses on the role of the polyunsaturated fatty acids in the human eye, particularly in such pathologies as dry eye, glaucoma, and macular degeneration, in which dietary PUFA supplementation can be a valid therapeutic aid.

Possible mechanisms of age-dependent decline in cellular function in c-kit+ cardiac progenitor cells.

Cardiovascular disease (CVD) represents the most rapidly rising morbidity and mortality worldwide, with costs exceeding 30 billion dollars annually in North America. This article is protected by copyright. All rights reserved

Decline in cellular function of aged mouse c-kit+ cardiac progenitor cells.

While autologous stem cell-based therapies are currently being tested on elderly patients, there are limited data on the function of aged stem cells and in particular c-kit+ cardiac progenitor cells (CPCs). We isolated c-kit+ cells from young (3months) and aged (24months) C57BL/6 mice to compare their biological properties. Aged CPCs have increased senescence, decreased stemness and reduced capacity to proliferate or to differentiate following dexamethasone (Dex) treatment in vitro, as evidenced by lack of cardiac lineage gene upregulation. Aged CPCs fail to activate mitochondrial biogenesis and increase proteins involved in mitochondrial oxidative phosphorylation in response to Dex. Aged CPCs fail to upregulate paracrine factors that are potentially important for proliferation, survival and angiogenesis in response to Dex. The results highlight marked differences between young and aged CPCs, which may impact future design of autologous stem cell-based therapies. Therapeutic use of c-kit+ cardiac progenitor cells (CPCs) is being evaluated for regenerative therapy in older patients with ischaemic heart failure. Our understanding of the biology of these CPCs has, however, largely come from studies of young cells and animal models. In the present study we examined characteristics of CPCs isolated from young (3months) and aged (24months) mice that could underlie the diverse outcomes reported for CPC-based therapeutics. We observed morphological differences and altered senescence indicated by increased senescence-associated markers β-galactosidase and p16 mRNA in aged CPCs. The aged CPCs also proliferated more slowly than their young counterparts and expressed lower levels of the stemness marker LIN28. We subsequently treated the cells with dexamethasone (Dex), routinely used to induce commitment in CPCs, for 7days and analysed expression of cardiac lineage marker genes. While MEF2C, GATA4, GATA6 and PECAM mRNAs were significantly upregulated in response to Dex treatment in young CPCs, their expression was not increased in aged CPCs. Interestingly, Dex treatment of aged CPCs also failed to increase mitochondrial biogenesis and expression of the mitochondrial proteins Complex III and IV, consistent with a defect in mitochondria complex assembly in the aged CPCs. Dex-treated aged CPCs also had impaired ability to upregulate expression of paracrine factor genes and the conditioned media from these cells had reduced ability to induce angiogenesis in vitro. These findings could impact the design of future CPC-based therapeutic approaches for the treatment of older patients suffering from cardiac injury.

Severe trauma in the geriatric population.

Geriatric trauma constitutes an increasingly recognized problem. Aging results in a progressive decline in cellular function which leads to a loose of their capacity to respond to injury. Some medications commonly used in this population can mask or blunt the response to injury. Falls constitute the most common cause of trauma and the leading cause of trauma-related deaths in this population. Falls are complicated by the widespread use of antiplatelets and anticoagulants, especially in patients with brain injury. Under-triage is common in this population. Evaluation of frailty could be helpful to solve this issue. Appropriate triaging and early aggressive management with correction of coagulopathy can improve outcome. Limitation of care and palliative measures must be considered in cases with a clear likelihood of poor prognosis.