bims-caglex 2024-05-19 papers

bims-caglex

Biomed News

on Cellular aging and life extension

Issue of 2024–05–19
23 papers selected by
Mario Alexander Guerra Patiño, Universidad Antonio Nariño

Hyperbaric oxygen therapy: future prospects in regenerative therapy and anti-aging.
AMPK as a mediator of tissue preservation: time for a shift in dogma?
In vitro heterochronic parabiosis identifies pigment epithelium-derived factor as a systemic mediator of rejuvenation by young blood.
Anti-aging Effects of Tirbanibulin 1% Ointment: A Real-Life Experience.
Circulating microRNA profile of long-lived Okinawans identifies novel potential targets for optimizing lifespan and health span.
Breaking down causes, consequences, and mediating effects of telomere length variation on human health.
Correction to "Rutin is a potent senomorphic agent to target senescent cells and can improve chemotherapeutic efficacy".
A novel mechanism of major ginsenosides from Panax ginseng against multiple organ aging in middle-aged mice: Phosphatidylcholine-myo-inositol metabolism based on metabolomic analysis.
Amino acid restriction, aging, and longevity: an update.
Mechanical stretch preconditioned adipose-derived stem cells elicit polarization of anti-inflammatory M2-like macrophages and improve chronic wound healing.
CCL4 contributes to aging related angiogenic insufficiency through activating oxidative stress and endothelial inflammation.
AMPK activation eliminates senescent cells in diabetic wound by inducing NCOA4 mediated ferritinophagy.
Synergistic impact of 25-hydroxyvitamin D concentrations and physical activity on delaying aging.
SIRT1 regulates the localization and stability of telomerase protein by direct interaction.
Post-translational modification-dependent oligomerization switch in regulation of global transcription and DNA damage repair during genotoxic stress.
Modulating the hAM/PCL Biocomposite for Expedited Wound Healing: A Chemical-Free Approach for Boosting Regenerative Potential.
Senolytic effects of exercise in human muscles require acute inflammation.
α-ketoglutarate preconditioning extends the survival of engrafted adipose-derived mesenchymal stem cells to accelerate healing of burn wounds.
Aging-Related Sarcopenia: Metabolic Characteristics and Therapeutic Strategies.
Sarcopenia: a dive into metabolism to promote a multimodal, preventive, and regenerative approach.
Urine-derived stem cells genetically modified with IGF1 improve muscle regeneration.
Muscle Psn gene combined with exercise contribute to healthy aging of skeletal muscle and lifespan by adaptively regulating Sirt1/PGC-1α and arm pathway.
Mitophagy in health and disease. Molecular mechanisms, regulatory pathways, and therapeutic implications.

Front Aging. 2024 ;5 1368982

Hyperbaric oxygen therapy: future prospects in regenerative therapy and anti-aging.

Manoj Gupta, Jaishriram Rathored.

  Hyperbaric Oxygen Therapy (HBOT) utilizes 100% oxygen at high atmospheric pressure for clinical applications. HBOT has proven to be an effective supplementary treatment for a variety of clinical and pathological disorders. HBOT's therapeutic results are based on the physiological effects of increased tissue oxygenation, or improved oxygen bioavailability. HBOT's current indications in illnesses like as wound healing, thermal or radiation burns, and tissue necrosis point to its function in facilitating the regeneration process. Various research has revealed that HBOT plays a function in vascularization, angiogenesis, and collagen production augmentation. Individual regeneration capacity is influenced by both environmental and genetic factors. Furthermore, the regenerating ability of different types of tissues varies, and this ability declines with age. HBOT affects physiological processes at the genetic level by altering gene expression, delaying cell senescence, and assisting in telomere length enhancement. The positive results in a variety of indications, ranging from tissue regeneration to better cognitive function, indicate that it has enormous potential in regenerative and anti-aging therapy.

Keywords:  aging; hyperbaric medicine; hyperoxia; regeneration; senescence; telomere

DOI:  https://doi.org/10.3389/fragi.2024.1368982
Nat Rev Endocrinol. 2024 May 17.

AMPK as a mediator of tissue preservation: time for a shift in dogma?

Henning Tim Langer, Maria Rohm, Marcus DaSilva Goncalves, Lykke Sylow.

Ground-breaking discoveries have established 5'-AMP-activated protein kinase (AMPK) as a central sensor of metabolic stress in cells and tissues. AMPK is activated through cellular starvation, exercise and drugs by either directly or indirectly affecting the intracellular AMP (or ADP) to ATP ratio. In turn, AMPK regulates multiple processes of cell metabolism, such as the maintenance of cellular ATP levels, via the regulation of fatty acid oxidation, glucose uptake, glycolysis, autophagy, mitochondrial biogenesis and degradation, and insulin sensitivity. Moreover, AMPK inhibits anabolic processes, such as lipogenesis and protein synthesis. These findings support the notion that AMPK is a crucial regulator of cell catabolism. However, studies have revealed that AMPK's role in cell homeostasis might not be as unidirectional as originally thought. This Review explores emerging evidence for AMPK as a promoter of cell survival and an enhancer of anabolic capacity in skeletal muscle and adipose tissue during catabolic crises. We discuss AMPK-activating interventions for tissue preservation during tissue wasting in cancer-associated cachexia and explore the clinical potential of AMPK activation in wasting conditions. Overall, we provide arguments that call for a shift in the current dogma of AMPK as a mere regulator of cell catabolism, concluding that AMPK has an unexpected role in tissue preservation.

DOI: https://doi.org/10.1038/s41574-024-00992-y
bioRxiv. 2024 May 05. pii: 2024.05.02.592258. [Epub ahead of print]

In vitro heterochronic parabiosis identifies pigment epithelium-derived factor as a systemic mediator of rejuvenation by young blood.

Xizhe Wang, Cagdas Tazearslan, Seungsoo Kim, Qinghua Guo, Daniela Contreras, Jiping Yang, Adam D Hudgins, Yousin Suh.

Several decades of heterochronic parabiosis (HCPB) studies have demonstrated the restorative impact of young blood, and deleterious influence of aged blood, on physiological function and homeostasis across tissues, although few of the factors responsible for these observations have been identified. Here we develop an in vitro HCPB system to identify these circulating factors, using replicative lifespan (RLS) of primary human fibroblasts as an endpoint of cellular health. We find that RLS is inversely correlated with serum donor age and sensitive to the presence or absence of specific serum components. Through in vitro HCPB, we identify the secreted protein pigment epithelium-derived factor (PEDF) as a circulating factor that extends RLS of primary human fibroblasts and declines with age in mammals. Systemic administration of PEDF to aged mice reverses age-related functional decline and pathology across several tissues, improving cognitive function and reducing hepatic fibrosis and renal lipid accumulation. Together, our data supports PEDF as a systemic mediator of the effect of young blood on organismal health and homeostasis and establishes our in vitro HCPB system as a valuable screening platform for the identification of candidate circulating factors involved in aging and rejuvenation.

DOI: https://doi.org/10.1101/2024.05.02.592258
Dermatol Ther (Heidelb). 2024 May 14.

Anti-aging Effects of Tirbanibulin 1% Ointment: A Real-Life Experience.

Federica Li Pomi, Lucia Peterle, Andrea d'Aloja, Antonio Di Tano, Mario Vaccaro, Francesco Borgia.

   INTRODUCTION: Tirbanibulin 1% ointment has been licensed to treat non-hyperkeratotic actinic keratosis (AKs) on the face and scalp in adults to ensure excellent patient tolerability due to the mild side effects and the brief application time compared to other topical therapies on the market. A growing body of evidence suggests that, beyond their primary function, the treatments for AKs and the cancerization field may inadvertently confer substantial cosmetic benefits to patients.
METHODS: We report a single-center retrospective case series of patients referred to the Dermatology Unit of the University Hospital of Messina, Italy, between February and December 2023 seeking treatment for AKs in the context of photodamaged areas in which the application of tirbanibulin 1% ointment induced, besides clearance of AKs, anti-aging effects on both skin texture and solar lentigos.
RESULTS: Seven patients affected by Olsen grade 1-2 AKs experienced a powerful rejuvenating effect in the treated areas, with a marked efficacy in skin lightening and clearance of solar lentigo.
CONCLUSIONS: Tirbanibulin 1% ointment seems able to improve skin aging as a desirable side effect at the site of application for AKs on chronic photodamaged skin. Such preliminary observation needs further confirmation in real-life studies on larger cohorts of patients, to explain the pathogenic mechanisms responsible for such aesthetically relevant results.

Keywords:  Actinic keratosis; Anti-aging; Rejuvenation; Solar lentigo; Tirbanibulin; Tirbanibulin ointment; Wrinkle

DOI:  https://doi.org/10.1007/s13555-024-01178-0
Aging Cell. 2024 May 15. e14191

Circulating microRNA profile of long-lived Okinawans identifies novel potential targets for optimizing lifespan and health span.

Sarah Noureddine, Augusto Schneider, Sydney Strader, Xiang Zhu, Joseph Dhahbi, Richard Allsopp, D Craig Willcox, Timothy A Donlon, Michio Shimabukuro, Moritake Higa, Makoto Suzuki, Trevor Torigoe, Sarah Ashiqueali, Hariom Yadav, Bradley J Willcox, Michal M Masternak.

  Nonagenarians and centenarians serve as successful examples of aging and extended longevity, showcasing robust regulation of biological mechanisms and homeostasis. Given that human longevity is a complex field of study that navigates molecular and biological mechanisms influencing aging, we hypothesized that microRNAs, a class of small noncoding RNAs implicated in regulating gene expression at the post-transcriptional level, are differentially regulated in the circulatory system of young, middle-aged, and nonagenarian individuals. We sequenced circulating microRNAs in Okinawan males and females <40, 50-80, and >90 years of age accounting for FOXO3 genetic variations of single nucleotide polymorphism (SNP) rs2802292 (TT - common vs. GT - longevity) and validated the findings through RT-qPCR. We report five microRNAs exclusively upregulated in both male and female nonagenarians with the longevity genotype, play predictive functional roles in TGF-β, FoxO, AMPK, Pi3K-Akt, and MAPK signaling pathways. Our findings suggest that these microRNAs upregulated in nonagenarians may provide novel insight into enhanced lifespan and health span. This discovery warrants further exploration into their roles in human aging and longevity.

Keywords:  FOXO3; Okinawan nonagenarians; aging; longevity; microRNAs

DOI:  https://doi.org/10.1111/acel.14191
Genome Biol. 2024 May 17. 25(1): 125

Breaking down causes, consequences, and mediating effects of telomere length variation on human health.

Samuel Moix, Marie C Sadler, Zoltán Kutalik, Chiara Auwerx.

   BACKGROUND: Telomeres form repeated DNA sequences at the ends of chromosomes, which shorten with each cell division. Yet, factors modulating telomere attrition and the health consequences thereof are not fully understood. To address this, we leveraged data from 326,363 unrelated UK Biobank participants of European ancestry.
RESULTS: Using linear regression and bidirectional univariable and multivariable Mendelian randomization (MR), we elucidate the relationships between leukocyte telomere length (LTL) and 142 complex traits, including diseases, biomarkers, and lifestyle factors. We confirm that telomeres shorten with age and show a stronger decline in males than in females, with these factors contributing to the majority of the 5.4% of LTL variance explained by the phenome. MR reveals 23 traits modulating LTL. Smoking cessation and high educational attainment associate with longer LTL, while weekly alcohol intake, body mass index, urate levels, and female reproductive events, such as childbirth, associate with shorter LTL. We also identify 24 traits affected by LTL, with risk for cardiovascular, pulmonary, and some autoimmune diseases being increased by short LTL, while longer LTL increased risk for other autoimmune conditions and cancers. Through multivariable MR, we show that LTL may partially mediate the impact of educational attainment, body mass index, and female age at childbirth on proxied lifespan.
CONCLUSIONS: Our study sheds light on the modulators, consequences, and the mediatory role of telomeres, portraying an intricate relationship between LTL, diseases, lifestyle, and socio-economic factors.

Keywords:  Aging; Complex traits; Female reproduction; Lifespan; Lifestyle; Mediation; Mendelian randomization; Telomeres; UK Biobank

DOI:  https://doi.org/10.1186/s13059-024-03269-9
Aging Cell. 2024 May 12. e14183

Correction to "Rutin is a potent senomorphic agent to target senescent cells and can improve chemotherapeutic efficacy".

DOI: https://doi.org/10.1111/acel.14183
Biochem Biophys Res Commun. 2024 May 09. pii: S0006-291X(24)00563-1. [Epub ahead of print]719 150027

A novel mechanism of major ginsenosides from Panax ginseng against multiple organ aging in middle-aged mice: Phosphatidylcholine-myo-inositol metabolism based on metabolomic analysis.

Mingyao E, Zepeng Zhang, Peng Ji, Qing Liu, Hongyu Qi, Tong Hou, Hang Su, Zeyu Wang, Xiangyan Li.

  Aging is a complex, degenerative process associated with various metabolic abnormalities. Ginsenosides (GS) is the main active components of Panax ginseng, which has anti-aging effects and improves metabolism. However, the anti-aging effect and the mechanism of GS in middle-aged mice has not been elucidated. In this study, GS after 3-month treatment significantly improved the grip strength, fatigue resistance, cognitive indices, and cardiac function of 15-month-old mice. Meanwhile, GS treatment reduced the fat content and obviously inhibited histone H2AX phosphorylation at Ser 139 (γ-H2AX), a marker of DNA damage in major organs, especially in the heart and liver. Further, the correlation analysis of serum metabolomics combined with aging phenotype suggested that myo-inositol (MI) upregulated by GS was positively correlated with left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS), the main indicators of cardiac function. More importantly, liver tissue metabolomic analysis showed that GS increased MI content by promoting the synthesis pathway from phosphatidylcholine (PC) to MI for the inhibition of liver aging. Finally, we proved that MI reduced the percentage of senescence-associated β-galactosidase staining, γ-H2AX immunofluorescence staining, p21 expression, and the production of reactive oxygen species in H2O2-induced cardiomyocytes. These results suggest that GS can enhance multiple organ functions, especially cardiac function for promoting the healthspan of aging mice, which is mediated by the conversion of PC to MI in the liver and the increase of MI level in the serum. Our study might provide new insights into the potential mechanisms of ginsenosides for prolonging the healthspan of natural aging mice.

Keywords:  Aging; Ginsenosides; Metabolism; Myo-inositol; Phosphatidylcholine

DOI:  https://doi.org/10.1016/j.bbrc.2024.150027
Front Aging. 2024 ;5 1393216

Amino acid restriction, aging, and longevity: an update.

S N Austad, J R Smith, J M Hoffman.

  Various so-called dietary restriction paradigms have shown promise for extending health and life. All such paradigms rely on ad libitum (hereafter ad lib) feeding, something virtually never employed in animals whose long-term health we value, either as a control or, except for food restriction itself, for both control and treatment arms of the experiment. Even though the mechanism(s) remain only vaguely understood, compared to ad lib-fed animals a host of dietary manipulations, including calorie restriction, low protein, methionine, branched-chain amino acids, and even low isoleucine have demonstrable health benefits in laboratory species in a standard laboratory environment. The remaining challenge is to determine whether these health benefits remain in more realistic environments and how they interact with other health enhancing treatments such as exercise or emerging geroprotective drugs. Here we review the current state of the field of amino acid restriction on longevity of animal models and evaluate its translational potential.

Keywords:  amino acid restriction; diet; food restriction; longevity; protein restriction

DOI:  https://doi.org/10.3389/fragi.2024.1393216
FASEB J. 2024 May 31. 38(10): e23626

Mechanical stretch preconditioned adipose-derived stem cells elicit polarization of anti-inflammatory M2-like macrophages and improve chronic wound healing.

Jiahao He, Shengzhou Shan, Taoran Jiang, Sizheng Zhou, Jiaqi Qin, Qingfeng Li, Zheyuan Yu, Dejun Cao, Bin Fang.

  Transplantation of adipose-derived stem cells (ASCs) is a promising option in the field of chronic wounds treatment. However, the effectiveness of ASCs therapies has been hampered by highly inflammatory environment in chronic wound areas. These problems could be partially circumvented using efficient approaches that boost the survival and anti-inflammatory capacity of transplanted ASCs. Here, by application of mechanical stretch (MS), we show that ASCs exhibits increased survival and immunoregulatory properties in vitro. MS triggers the secretion of macrophage colony stimulating factor (M-CSF) from ASCs, a chemokine that is linked to anti-inflammatory M2-like macrophages polarization. When the MS-ASCs were transplanted to chronic wounds, the wound area yields significantly faster closure rate and lower inflammatory mediators, largely due to macrophages polarization driven by transplanted MS-ASCs. Thus, our work shows that mechanical stretch can be harnessed to enhance ASCs transplantation efficiency in chronic wounds treatment.

Keywords:  adipose‐derived stem cells; anti‐inflammatory M2‐like macrophages; chronic wounds; mechanical stretch

DOI:  https://doi.org/10.1096/fj.202300586R
Angiogenesis. 2024 May 13.

CCL4 contributes to aging related angiogenic insufficiency through activating oxidative stress and endothelial inflammation.

Ting-Ting Chang, Liang-Yu Lin, Ching Chen, Jaw-Wen Chen.

  Aging is a natural process associated with chronic inflammation in the development of vascular dysfunction. We hypothesized that chemokine C-C motif ligands 4 (CCL4) might play a vital role in aging-related vascular dysfunction. Circulating CCL4 was up-regulated in elderly subjects and in aged animals. CCL4 inhibition reduced generation of reactive oxygen species (ROS), attenuated inflammation, and restored cell functions in endothelial progenitor cells from elderly subjects and in aged human aortic endothelial cells. CCL4 promoted cell aging, with impaired cell functioning, by activating ROS production and inflammation. CCL4 knockout mice and therapeutic administration of anti-CCL4 neutralizing antibodies exhibited vascular and dermal anti-aging effects, with improved wound healing, via the down-regulation of inflammatory proteins and the activation of angiogenic proteins. Altogether, our findings suggested that CCL4 may contribute to aging-related vascular dysfunction via activating oxidative stress and endothelial inflammation. CCL4 may be a potential therapeutic target for vascular protections during aging.

Keywords:  Aging; CCL4; Inflammation; Oxidative stress; Vascular dysfunction

DOI:  https://doi.org/10.1007/s10456-024-09922-y
Mol Med. 2024 May 17. 30(1): 63

AMPK activation eliminates senescent cells in diabetic wound by inducing NCOA4 mediated ferritinophagy.

Mengqian Liu, Xuerong Wei, Zijun Zheng, Erlian Xie, Qiuyi Yu, Yanbin Gao, Jun Ma, Lei Yang.

   BACKGROUND: Diabetic wounds are one of the long-term complications of diabetes, with a disordered microenvironment, diabetic wounds can easily develop into chronic non-healing wounds, which can impose a significant burden on healthcare. In diabetic condition, senescent cells accumulate in the wound area and suppress the wound healing process. AMPK, as a molecule related to metabolism, has a close relationship with aging and diabetes. The purpose of this study was to investigate the effects of AMPK activation on wound healing and explore the underlying mechanisms.
METHODS: AMPK activator A769662 was topically applied in wound models of diabetic mice. Alterations in the wound site were observed and analyzed by immunohistochemistry. The markers related to autophagy and ferritinophagy were analyzed by western blotting and immunofluorescence staining. The role of AMPK activation and ferritinophagy were also analyzed by western blotting.
RESULTS: Our results show that AMPK activation improved diabetic wound healing and reduced the accumulation of senescent cells. Intriguingly, we found that AMPK activation-induced ferroptosis is autophagy-dependent. We detected that the level of ferritin had deceased and NCOA4 was markedly increased after AMPK activation treatment. We further investigated that NCOA4-mediated ferritinophagy was involved in ferroptosis triggered by AMPK activation. Most importantly, AMPK activation can reverse the ferroptosis-insensitive of senescent fibroblast cells in diabetic mice wound area and promote wound healing.
CONCLUSIONS: These results suggest that activating AMPK can promote diabetic wound healing by reversing the ferroptosis-insensitive of senescent fibroblast cells. AMPK may serve as a regulatory factor in senescent cells in the diabetic wound area, therefore AMPK activation can become a promising therapeutic method for diabetic non-healing wounds.

Keywords:  AMPK; Autophagy; Cellular senescence; Diabetic wound; Ferroptosis

DOI:  https://doi.org/10.1186/s10020-024-00825-8
Redox Biol. 2024 May 10. pii: S2213-2317(24)00166-6. [Epub ahead of print]73 103188

Synergistic impact of 25-hydroxyvitamin D concentrations and physical activity on delaying aging.

Chang Liu, Lin Hua, Zhong Xin.

   OBJECTIVE: Our study aims to examine the independent and combined associations of serum 25-hydroxyvitamin D [25(OH)D] concentrations and physical activity (PA) status with phenotypic age (PhenoAge).
METHOD: The analysis included 18,738 participants from the NHANES 2007-2010 & 2015-2018. Phenotypic Age Acceleration (PhenoAgeAccel) was calculated as the residuals from regressing PhenoAge on chronological age. Weighted multivariable logistic regression models were used to analysis the relationship between 25(OH)D and PA with PhenoAgeAccel. Population attributable fraction (PAF) was used to estimate the proportion of PhenoAgeAccel which could be avoided if exposure were eliminated.
RESULTS: The multivariate-adjusted OR (95%CI) for PhenoAgeAccel with high 25(OH)D and adequate PA were 0.657 (0.549,0.787) (p < 0.001) for all, 0.663 (0.538,0.818) (p < 0.001) for participants whose age ≤65years old. Furthermore, there was multiplicative interaction between 25(OH)D and PA in age ≤65 years old group (0.729 (0.542,0.979), p = 0.036). High 25(OH)D level and adequate PA reduced the risk of PhenoAgeAccel by 14.3 % and 14.2 %, respectively. Notably, 30.7 % decrease was attributable to both high 25(OH)D level and engaging in adequate PA concurrently. Combining 25(OH)D above 80.4 nmol/l with PA decreased PhenoAge by 1.291 years (p < 0.001).
CONCLUSION: Higher 25(OH)D level was associated with lower risk of biological ageing. Combining 25(OH)D and PA demonstrated enhanced protective effects, especially in middle or young adults. These findings underscore the importance of outdoor PA in slowing down the aging process.

Keywords:  Aging acceleration; Joint association; Phenotypic age; Physical activity; Vitamin D

DOI:  https://doi.org/10.1016/j.redox.2024.103188
Biochem Biophys Res Commun. 2024 May 11. pii: S0006-291X(24)00634-X. [Epub ahead of print]720 150098

SIRT1 regulates the localization and stability of telomerase protein by direct interaction.

Seung Eon Lee, Su Bin Lee, Jae-Il Roh, Kwang Pyo Kim, Jae Hoon Lee, Han-Woong Lee.

  Telomerase reverse transcriptase (TERT) not only upholds telomeric equilibrium but also plays a pivotal role in multiple non-canonical cellular mechanisms, particularly in the context of aging, cancer, and genomic stability. Though depletion of SIRT1 in mouse embryonic fibroblasts has demonstrated telomere shortening, the impact of SIRT1 on enabling TERT to regulate telomeric homeostasis remains enigmatic. Here, we reveal that SIRT1 directly interacts with TERT, and promotes the nuclear localization and stability of TERT. Reverse transcriptase (RT) domain of TERT and N-terminus of SIRT1 mainly participated in their direct interaction. TERT, concomitantly expressed with intact SIRT1, exhibits nuclear localization, whereas TERT co-expressed with N-terminal-deleted SIRT1 remains in the cytosol. Furthermore, overexpression of SIRT1 enhances the nuclear localization and protein stability of TERT, akin to overexpression of deacetylase-inactive SIRT1, whereas N-terminal-deleted SIRT1 has no effect on TERT. These findings suggest a novel regulatory role of SIRT1 for TERT through direct interaction. This interaction provides new insights into the fields of aging, cancer, and genome stability governed by TERT and SIRT1.

Keywords:  Protein localization; Protein stability; Protein-protein interaction; SIRT1; Telomerase reverse transcriptase

DOI:  https://doi.org/10.1016/j.bbrc.2024.150098
Nat Commun. 2024 May 15. 15(1): 4128

Post-translational modification-dependent oligomerization switch in regulation of global transcription and DNA damage repair during genotoxic stress.

Prathama Talukdar, Sujay Pal, Debabrata Biswas.

Mechanisms of functional cross-talk between global transcriptional repression and efficient DNA damage repair during genotoxic stress are poorly known. In this study, using human AF9 as representative of Super Elongation Complex (SEC) components, we delineate detailed mechanisms of these processes. Mechanistically, we describe that Poly-Serine domain-mediated oligomerization is pre-requisite for AF9 YEATS domain-mediated TFIID interaction-dependent SEC recruitment at the promoter-proximal region for release of paused RNA polymerase II. Interestingly, during genotoxic stress, CaMKII-mediated phosphorylation-dependent nuclear export of AF9-specific deacetylase HDAC5 enhances concomitant PCAF-mediated acetylation of K339 residue. This causes monomerization of AF9 and reduces TFIID interaction for transcriptional downregulation. Furthermore, the K339 acetylation-dependent enhanced AF9-DNA-PKc interaction leads to phosphorylation at S395 residue which reduces AF9-SEC interaction resulting in transcriptional downregulation and efficient repair of DNA damage. After repair, nuclear re-entry of HDAC5 reduces AF9 acetylation and restores its TFIID and SEC interaction to restart transcription.

DOI: https://doi.org/10.1038/s41467-024-48530-8
ACS Biomater Sci Eng. 2024 May 16.

Modulating the hAM/PCL Biocomposite for Expedited Wound Healing: A Chemical-Free Approach for Boosting Regenerative Potential.

Pinky, Aarushi Sharma, Varun Arora, E Pranshu Rao, Sudheer Arava, Ashwini K Agrawal, Manjeet Jassal, Sujata Mohanty.

  There is an arising need for effective wound dressings that retain the bioactivity of a cellular treatment, but without the high costs and complexities associated with manufacturing, storing, and applying cell-based products. As skin wound recovery is a dynamic and complicated process, a significant obstacle to the healing of skin wounds is the lack of an appropriate wound dressing that can imitate the microenvironment of healthy skin and prevent bacterial infection. It requires the well-orchestrated integration of biological and molecular events. In this study, we have fabricated full-thickness skin graft biocomposite membranes to target full-thickness skin excision wounds. We reinforced human amniotic membrane (hAM) with electrospun polycaprolactone (PCL) to develop composite membranes, namely, PCL/hAM and PCL/hAM/PCL. Composite membranes were compared for physical, biological, and mechanical properties with the native counterpart. PCL/hAM and PCL/hAM/PCL displayed improved stability and delayed degradation, which further synergically improved the rapid wound healing property of hAM, driven primarily by wound closure analysis and histological assessment. Moreover, PCL/hAM displayed a comparable cellular interaction to hAM. On application as a wound dressing, histological analysis demonstrated that hAM and PCL/hAM promoted early epidermis and dermis formation. Studies on in vivo wound healing revealed that although hAM accelerates cell development, the overall wound healing process is similar in PCL/hAM. This finding is further supported by the immunohistochemical analysis of COL-1/COL-3, CD-31, and TGF-β. Overall, this conjugated PCL and hAM-based membrane has considerable potential to be applied in skin wound healing. The facile fabrication of the PCL/hAM composite membrane provided the self-regenerating wound dressing with the desired mechanical strength as an ideal regenerative property for skin tissue regeneration.

Keywords:  PCL; composite membrane; electrospinning; full-thickness excision wound; human amniotic membrane; skin wound healing

DOI:  https://doi.org/10.1021/acsbiomaterials.3c01740
Aging (Albany NY). 2024 May 15. 16

Senolytic effects of exercise in human muscles require acute inflammation.

Wei-Horng Jean, Yin-Chou Lin, Pei-Yao Ang, Kazushige Goto, Chao-An Lin, Luthfia Dewi, Yu-Chieh Liao, Chih-Yang Huang, Chia-Hua Kuo.

  Higher intensity exercise, despite causing more tissue damage, improved aging conditions. We previously observed decreased p16INK4a mRNA in human skeletal muscle after high-intensity interval exercise (HIIE), with no change following equivalent work in moderate-intensity continuous exercise. This raises the question of whether the observed senolytic effect of exercise is mediated by inflammation, an immune response induced by muscle damage. In this study, inflammation was blocked using a multiple dose of ibuprofen (total dose: 1200 mg), a commonly consumed nonsteroidal anti-inflammatory drug (NSAID), in a placebo-controlled, counterbalanced crossover trial. Twelve men aged 20-26 consumed ibuprofen or placebo before and after HIIE at 120% maximum aerobic power. Multiple muscle biopsies were taken for tissue analysis before and after HIIE. p16INK4a+ cells were located surrounding myofibers in muscle tissues. The maximum decrease in p16INK4a mRNA levels within muscle tissues occurred at 3 h post-exercise (-82%, p < 0.01), gradually recovering over the next 3-24 h. A concurrent reduction pattern in CD11b mRNA (-87%, p < 0.01) was also found within the same time frame. Ibuprofen treatment attenuated the post-exercise reduction in both p16INK4a mRNA and CD11b mRNA. The strong correlation (r = 0.88, p < 0.01) between p16INK4a mRNA and CD11b mRNA in muscle tissues suggests a connection between the markers of tissue aging and pro-inflammatory myeloid differentiation. In conclusion, our results suggest that the senolytic effect of high-intensity exercise on human skeletal muscle is mediated by acute inflammation.

Keywords:  NSAID; cellular senescence; high-intensity intermittent exercise; inflammation; p16INK4a

DOI:  https://doi.org/10.18632/aging.205827
Exp Cell Res. 2024 May 15. pii: S0014-4827(24)00186-1. [Epub ahead of print] 114095

α-ketoglutarate preconditioning extends the survival of engrafted adipose-derived mesenchymal stem cells to accelerate healing of burn wounds.

Shuaijun Li, Cheng Zhao, Guoying Shang, Jun-Ling Xie, Lei Cui, Qun Zhang, Jiefeng Huang.

  The application of adipose-derived stem cells (ADSCs) in treating hard-to-heal wounds has been widely accepted, while the short-term survival rate remains an obstacle in stem cell therapy. The aim of this study is to investigate the effect of preconditioning ADSCs with α-ketoglutarate (α-KG) on the healing of acid burn wounds and cell survival within wounds. Preconditioning of ADSCs was performed by treating cells at passage 3 with 3.5 mM DM-αKG for 24 hours. Proliferation and migration of ADSCs was examined. An acid burn wound was created on the dorsal skin of mice. Cell suspension of ADSCs (2 ×106 cells/ml), either pre-treated with α-KG or not, was injected subcutaneously around the margin of wound. At 1,4,7,10,14 days after injection, the percentage of wound closure was evaluated. Expression of pro-angiogenic factors, matrix molecules and HIF1-α in pretreated ADSCs or in wounds was evaluated by qRT-PCR and immunohistochemistry staining, respectively. The survival rate of DiO-labelled ADSCs was determined with the in vivo bioluminescent imaging system. Treating with α-KG induced an enhancement in migration of ADSCs, while their proliferation was not affected. Expression of Vegf and Fgf-2 was significantly increased. With injection of pretreated ADSCs, healing of wounds was remarkably accelerated, along with increased ECM deposition and microvessel density. Moreover, pretreatment with α-KG resulted a prolonged survival of engrafted ADSCs was observed. Expression of HIF-1α was significantly increased in ADSCs treated with α-KG and in wounds injected with preconditioned ADSCs. Our results revealed that healing of acid burn wound was accelerated with administration of ADSCs pretreated with α-KG, which induced elevated expression of HIF-1α and prolonged survival of engrafted stem cells.

Keywords:  Acidic burn; Adipose-derived stem cells; Survive; Wound healing; α-ketoglutarate

DOI:  https://doi.org/10.1016/j.yexcr.2024.114095
Aging Dis. 2024 Apr 19.

Aging-Related Sarcopenia: Metabolic Characteristics and Therapeutic Strategies.

Yonglian Chen, Jinhui Wu.

The proportion of the elderly population is gradually increasing as a result of medical care advances, leading to a subsequent surge in geriatric diseases that significantly impact quality of life and pose a substantial healthcare burden. Sarcopenia, characterized by age-related decline in skeletal muscle mass and quality, affects a considerable portion of older adults, particularly the elderly, and can result in adverse outcomes such as frailty, fractures, bedridden, hospitalization, and even mortality. Skeletal muscle aging is accompanied by underlying metabolic changes. Therefore, elucidating these metabolic profiles and specific mechanisms holds promise for informing prevention and treatment strategies for sarcopenia. This review provides a comprehensive overview of the key metabolites identified in current clinical studies on sarcopenia and their potential pathophysiological alterations in metabolic activity. Besides, we examine potential therapeutic strategies for sarcopenia from a perspective focused on metabolic regulation.

DOI: https://doi.org/10.14336/AD.2024.0407
Mech Ageing Dev. 2024 May 13. pii: S0047-6374(24)00041-1. [Epub ahead of print] 111941

Sarcopenia: a dive into metabolism to promote a multimodal, preventive, and regenerative approach.

Virginia Boccardi.

  Sarcopenia, the age-related loss of skeletal muscle mass and function, poses a significant challenge in the field of gerontology, impacting the health and independence of older adults. By synthesizing current research findings and theoretical frameworks, this perspective elucidates the multifaceted mechanisms underlying sarcopenia, mainly focusing on energy balance and metabolic processes. Furthermore, the manuscript explores the implications of sarcopenia on overall health outcomes, functional decline, and quality of life in older individuals.

Keywords:  Frailty; aging; metabolism; sarcopenia

DOI:  https://doi.org/10.1016/j.mad.2024.111941
Am J Clin Exp Urol. 2024 ;12(2): 64-87

Urine-derived stem cells genetically modified with IGF1 improve muscle regeneration.

Hualin Yi, Gang Chen, Shuai Qiu, Joshua T Maxwell, Guiting Lin, Tracy Criswell, Yuanyuan Zhang.

   OBJECTIVE: In this study we aimed to determine the impact of human urine derived stem cells (USC) and genetically modified USC that were designed to overexpress myogenic growth factor IGF1 (USCIGF), on the regenerative capacity of cardiotoxin (CTX)-injured murine skeletal muscle.
METHODS: We overexpressed IGF1 in USC and investigated the alterations in myogenic capacity and regenerative function in cardiotoxin-injured muscle tissues.
RESULTS: Compared with USC alone, USCIGF1 activated the IGF1-Akt-mTOR signaling pathway, significantly improved myogenic differentiation capacity in vitro, and enhanced the secretion of myogenic growth factors and cytokines. In addition, IGF1 overexpression increased the ability of USC to fuse with skeletal myocytes to form myotubes, regulated the pro-regenerative immune response and inflammatory cytokines, and increased myogenesis in an in vivo model of skeletal muscle injury.
CONCLUSION: Overall, USC genetically modified to overexpress IGF1 significantly enhanced skeletal muscle regeneration by regulating myogenic differentiation, paracrine effects, and cell fusion, as well as by modulating immune responses in injured skeletal muscles in vivo. This study provides a novel perspective for evaluating the myogenic function of USC as a nonmyogenic cell source in skeletal myogenesis. The combination of USC and IGF1 expression has the potential to provide a novel efficient therapy for skeletal muscle injury and associated muscular defects in patients with urinary incontinence.

Keywords:  IGF1; Urine derived stem cells; cell fusion; skeletal muscle; stem cell therapy; urinary incontinence

DOI:  https://doi.org/10.62347/QSKH2686
PLoS One. 2024 ;19(5): e0300787

Muscle Psn gene combined with exercise contribute to healthy aging of skeletal muscle and lifespan by adaptively regulating Sirt1/PGC-1α and arm pathway.

Ying-Hui Gao, Deng-Tai Wen, Zhong-Rui Du, Jing-Feng Wang, Shi-Jie Wang.

The Presenilin (Psn) gene is closely related to aging, but it is still unclear the role of Psn genes in skeletal muscle. Here, the Psn-UAS/Mhc-GAL4 system in Drosophila was used to regulate muscle Psn overexpression(MPO) and muscle Psn knockdown(MPK). Drosophila were subjected to endurance exercise from 4 weeks to 5 weeks old. The results showed that MPO and exercise significantly increased climbing speed, climbing endurance, lifespan, muscle SOD activity, Psn expression, Sirt1 expression, PGC-1α expression, and armadillo (arm) expression in aged Drosophila, and they significantly decreased muscle malondialdehyde levels. Interestingly, when the Psn gene is knockdown by 0.78 times, the PGC-1α expression and arm expression were also down-regulated, but the exercise capacity and lifespan were increased. Furthermore, exercise combined with MPO further improved the exercise capacity and lifespan. MPK combined with exercise further improves the exercise capacity and lifespan. Thus, current results confirmed that the muscle Psn gene was a vital gene that contributed to the healthy aging of skeletal muscle since whether it was overexpressed or knocked down, the aging progress of skeletal muscle structure and function was slowed down by regulating the activity homeostasis of Sirt1/PGC-1α pathway and Psn/arm pathway. Exercise enhanced the function of the Psn gene to delay skeletal muscle aging by up regulating the activity of the Sirt1/PGC-1α pathway and Psn/arm pathway.

DOI: https://doi.org/10.1371/journal.pone.0300787
Apoptosis. 2024 May 17.

Mitophagy in health and disease. Molecular mechanisms, regulatory pathways, and therapeutic implications.

Mark S D'Arcy.

  Mitophagy, a specialised form of autophagy, selectively targeting damaged or dysfunctional mitochondria, and is crucial for maintaining cellular homeostasis and mitochondrial quality control. Dysregulation of mitophagy contributes to various pathological conditions, including cancer, neurodegenerative and cardiovascular diseases. This review presents a comprehensive analysis of the molecular mechanisms, regulatory pathways, and interplay with other cellular processes governing mitophagy, emphasizing its importance in physiological and pathological contexts. We explore the PINK1/Parkin-mediated and receptor-mediated mitophagy pathways, encompassing BNIP3/NIX, FUNDC1, and Bcl2-L-13. Additionally, we discuss post-translational modifications and cellular signalling pathways modulating mitophagy, as well as the connection between mitophagy and ageing, highlighting the decline in mitophagy efficiency and its impact on age-related pathologies. The review also investigates mitophagy's role in human diseases such as cancer, myocardial ischemia-reperfusion injury, Parkinson's, and Alzheimer's disease. We assess the potential of mitophagy-targeting therapeutic strategies, focusing on the development of dietary therapies, small molecules, drugs, and gene therapy approaches that modulate mitophagy levels and efficiency for treating these diseases and dysfunctions commonly observed in ageing individuals. In summary, this review offers an extensive overview of the molecular mechanisms and regulatory networks involved in mitophagy, its association with autophagy, and implications in human health and disease. By examining the potential of mitophagy-modulating therapies in disease and non-disease settings, we aim to inspire further research to develop innovative treatment strategies for various pathological conditions linked to mitochondrial dysfunction and to ageing.

Keywords:  Ageing; Autophagy; Mitophagy

DOI:  https://doi.org/10.1007/s10495-024-01977-y