bims-cesemi 2024-04-14 papers

bims-cesemi

Biomed News

on Cellular senescence and mitochondria

Issue of 2024–04–14
fourteen papers selected by
Julio Cesar Cardenas, Universidad Mayor

Single-cell senescence identification reveals senescence heterogeneity, trajectory, and modulators.
INHBA regulates Hippo signaling to confer 5-FU chemoresistance mediated by cellular senescence in colon cancer cells.
Accelerated Aging Induced by an Unhealthy High-Fat Diet: Initial Evidence for the Role of Nrf2 Deficiency and Impaired Stress Resilience in Cellular Senescence.
Resveratrol activates autophagy and protects from UVA-induced photoaging in human skin fibroblasts and the skin of male mice by regulating the AMPK pathway.
Energy metabolism as therapeutic target for aged wound repair by engineered extracellular vesicle.
Frontiers in sarcopenia: Advancements in diagnostics, molecular mechanisms, and therapeutic strategies.
Successful Management of Chronic Wounds by an Autophagy-Activating Magnetized Water-Based Gel in Elderly Patients: A Case Series.
Integrin αvβ3 Upregulation in Response to Nutrient Stress Promotes Lung Cancer Cell Metabolic Plasticity.
Evidence of a pan-tissue decline in stemness during human aging.
Mitochondrial Ca2+ signaling is a hallmark of specific adipose tissue-cancer crosstalk.
Mrs2-mediated mitochondrial magnesium uptake is essential for the regulation of MCU-mediated mitochondrial Ca2+ uptake and viability.
An Innovative Mitochondrial-targeted Gene Therapy for Cancer Treatment.
Differential mitochondrial bioenergetics and cellular resilience in astrocytes, hepatocytes, and fibroblasts from aging baboons.
Muscle mitochondrial bioenergetic capacities are associated with multimorbidity burden in older adults: the Study of Muscle, Mobility and Aging (SOMMA).

Cell Metab. 2024 Apr 08. pii: S1550-4131(24)00088-3. [Epub ahead of print]

Single-cell senescence identification reveals senescence heterogeneity, trajectory, and modulators.

Wanyu Tao, Zhengqing Yu, Jing-Dong J Han.

  Cellular senescence underlies many aging-related pathologies, but its heterogeneity poses challenges for studying and targeting senescent cells. We present here a machine learning program senescent cell identification (SenCID), which accurately identifies senescent cells in both bulk and single-cell transcriptome. Trained on 602 samples from 52 senescence transcriptome datasets spanning 30 cell types, SenCID identifies six major senescence identities (SIDs). Different SIDs exhibit different senescence baselines, stemness, gene functions, and responses to senolytics. SenCID enables the reconstruction of senescent trajectories under normal aging, chronic diseases, and COVID-19. Additionally, when applied to single-cell Perturb-seq data, SenCID helps reveal a hierarchy of senescence modulators. Overall, SenCID is an essential tool for precise single-cell analysis of cellular senescence, enabling targeted interventions against senescent cells.

Keywords:  computational tool; senescence; senescence identification; senescence quantification; senescence regulators; single cell; trajectory

DOI:  https://doi.org/10.1016/j.cmet.2024.03.009
Int J Biochem Cell Biol. 2024 Apr 06. pii: S1357-2725(24)00061-X. [Epub ahead of print] 106570

INHBA regulates Hippo signaling to confer 5-FU chemoresistance mediated by cellular senescence in colon cancer cells.

Zhan Zhang, Lili Chen, Qiao Yang, Xiaowan Tang, Jianhua Li, Guangwen Zhang, Youqun Wang, Hui Huang.

  Colon cancer has become a global public health challenge, and 5-Fluorouracil (5-FU) chemoresistance is a major obstacle in its treatment. Chemoresistance can be mediated by therapy-induced cellular senescence. This study intended to investigate mechanisms of INHBA (inhibin A) in 5-FU resistance mediated by cellular senescence in colon cancer. Bioinformatics analysis of INHBA expression in colon cancer tissues, survival analysis, and correlation analysis of cellular senescence markers were performed. The effects of INHBA on the biological characteristics and 5-FU resistance of colon cancer cells were examined through loss/gain-of-function and molecular assays. Finally, a xenograft mouse model was built to validate the mechanism of INHBA in vivo. INHBA was upregulated in colon cancer and was significantly positively correlated with cellular senescence markers uncoupling protein 2 (UCP-2), matrix metalloproteinase-1 (MMP-1), dense and erect panicle 1 (DEP1), and p21. Cellular senescence in colon cancer mediated 5-FU resistance. Downregulation of INHBA expression enhanced 5-FU sensitivity in colon cancer cells, inhibited cell proliferation, promoted apoptosis, increased the proportion of cells in G0/G1 phase, and it resulted in a lower proportion of senescent cells and lower levels of the cellular senescence markers interleukin 6 (IL-6) and interleukin 8 (IL-8). Analysis of whether to use the pathway inhibitor Verteporfin proved that INHBA facilitated colon cancer cell senescence and enhanced 5-FU chemoresistance via inactivation of Hippo signaling pathway, and consistent results were obtained in vivo. Collectively, INHBA conferred 5-FU chemoresistance mediated by cellular senescence in colon cancer cells through negative regulation of Hippo signaling.

Keywords:  5-FU resistance; Hippo signaling; INHBA; cellular senescence in colon cancer

DOI:  https://doi.org/10.1016/j.biocel.2024.106570
Nutrients. 2024 Mar 26. pii: 952. [Epub ahead of print]16(7):

Accelerated Aging Induced by an Unhealthy High-Fat Diet: Initial Evidence for the Role of Nrf2 Deficiency and Impaired Stress Resilience in Cellular Senescence.

Priya Balasubramanian, Tamas Kiss, Rafal Gulej, Adam Nyul Toth, Stefano Tarantini, Andriy Yabluchanskiy, Zoltan Ungvari, Anna Csiszar.

  High-fat diets (HFDs) have pervaded modern dietary habits, characterized by their excessive saturated fat content and low nutritional value. Epidemiological studies have compellingly linked HFD consumption to obesity and the development of type 2 diabetes mellitus. Moreover, the synergistic interplay of HFD, obesity, and diabetes expedites the aging process and prematurely fosters age-related diseases. However, the underlying mechanisms driving these associations remain enigmatic. One of the most conspicuous hallmarks of aging is the accumulation of highly inflammatory senescent cells, with mounting evidence implicating increased cellular senescence in the pathogenesis of age-related diseases. Our hypothesis posits that HFD consumption amplifies senescence burden across multiple organs. To scrutinize this hypothesis, we subjected mice to a 6-month HFD regimen, assessing senescence biomarker expression in the liver, white adipose tissue, and the brain. Aging is intrinsically linked to impaired cellular stress resilience, driven by dysfunction in Nrf2-mediated cytoprotective pathways that safeguard cells against oxidative stress-induced senescence. To ascertain whether Nrf2-mediated pathways shield against senescence induction in response to HFD consumption, we explored senescence burden in a novel model of aging: Nrf2-deficient (Nrf2+/-) mice, emulating the aging phenotype. Our initial findings unveiled significant Nrf2 dysfunction in Nrf2+/- mice, mirroring aging-related alterations. HFD led to substantial obesity, hyperglycemia, and impaired insulin sensitivity in both Nrf2+/- and Nrf2+/+ mice. In control mice, HFD primarily heightened senescence burden in white adipose tissue, evidenced by increased Cdkn2a senescence biomarker expression. In Nrf2+/- mice, HFD elicited a significant surge in senescence burden across the liver, white adipose tissue, and the brain. We postulate that HFD-induced augmentation of senescence burden may be a pivotal contributor to accelerated organismal aging and the premature onset of age-related diseases.

Keywords:  ageing; endothelial cells; high-fat diet; obesity; prediabetes; senescence; stress resistance; unhealthy diet

DOI:  https://doi.org/10.3390/nu16070952
Biogerontology. 2024 Apr 09.

Resveratrol activates autophagy and protects from UVA-induced photoaging in human skin fibroblasts and the skin of male mice by regulating the AMPK pathway.

Yangmin Xia, Hao Zhang, Xiangyi Wu, Ye Xu, Qian Tan.

  Skin photoaging is mostly caused by ultraviolet A (UVA), although active medications to effectively counteract UVA-induced photoaging have not yet been created. Resveratrol, a naturally occurring polyphenol found in the skin of grapes, has been shown to have various biological functions such as anti-inflammatory and antioxidant characteristics. However, the role of resveratrol in UVA-induced photoaging has not been clarified. We investigated the mechanism of action of resveratrol by UVA irradiation of human skin fibroblasts (HSF) and innovatively modified a mouse model of photoaging. The results demonstrated that resveratrol promoted AMP-activated protein kinase (AMPK) phosphorylation to activate autophagy, reduce reactive oxygen species (ROS) production, inhibit apoptosis, and restore normal cell cycle to alleviate UVA-induced photoaging. In addition, subcutaneous injection of resveratrol not only improved the symptoms of roughness, erythema, and increased wrinkles in the skin of UVA photodamaged mice, but also alleviated epidermal hyperkeratosis and hyperpigmentation, reduced inflammatory responses, and inhibited collagen fiber degradation. In conclusion, our studies proved that resveratrol can treat UVA-induced photoaging and elucidated the possible molecular mechanisms involved, providing a new therapeutic strategy for future anti-aging.

Keywords:  AMPK; Autophagy; Photoaging; ROS; Resveratrol; UVA

DOI:  https://doi.org/10.1007/s10522-024-10099-6
Sci Adv. 2024 Apr 12. 10(15): eadl0372

Energy metabolism as therapeutic target for aged wound repair by engineered extracellular vesicle.

Yu Zhuang, Shengjie Jiang, Xiaoling Deng, An Lao, Xiaolin Hua, Yun Xie, Lingyong Jiang, Xudong Wang, Kaili Lin.

Aging skin, vulnerable to age-related defects, is poor in wound repair. Metabolic regulation in accumulated senescent cells (SnCs) with aging is essential for tissue homeostasis, and adequate ATP is important in cell activation for aged tissue repair. Strategies for ATP metabolism intervention hold prospects for therapeutic advances. Here, we found energy metabolic changes in aging skin from patients and mice. Our data show that metformin engineered EV (Met-EV) can enhance aged mouse skin repair, as well as ameliorate cellular senescence and restore cell dysfunctions. Notably, ATP metabolism was remodeled as reduced glycolysis and enhanced OXPHOS after Met-EV treatment. We show Met-EV rescue senescence-induced mitochondria dysfunctions and mitophagy suppressions, indicating the role of Met-EV in remodeling mitochondrial functions via mitophagy for adequate ATP production in aged tissue repair. Our results reveal the mechanism for SnCs rejuvenation by EV and suggest the disturbed energy metabolism, essential in age-related defects, to be a potential therapeutic target for facilitating aged tissue repair.

DOI: https://doi.org/10.1126/sciadv.adl0372
Mol Aspects Med. 2024 Apr 06. pii: S0098-2997(24)00029-3. [Epub ahead of print]97 101270

Frontiers in sarcopenia: Advancements in diagnostics, molecular mechanisms, and therapeutic strategies.

Dequan Liu, Shijin Wang, Shuang Liu, Qifei Wang, Xiangyu Che, Guangzhen Wu.

  The onset of sarcopenia is intimately linked with aging, posing significant implications not only for individual patient quality of life but also for the broader societal healthcare framework. Early and accurate identification of sarcopenia and a comprehensive understanding of its mechanistic underpinnings and therapeutic targets paramount to addressing this condition effectively. This review endeavors to present a cohesive overview of recent advancements in sarcopenia research and diagnosis. We initially delve into the contemporary diagnostic criteria, specifically referencing the European Working Group on Sarcopenia in Older People (EWGSOP) 2 and Asian Working Group on Sarcopenia (AWGS) 2019 benchmarks. Additionally, we elucidate comprehensive assessment techniques for muscle strength, quantity, and physical performance, highlighting tools such as grip strength, chair stand test, dual-energy X-ray Absorptiometry (DEXA), bioelectrical impedance analysis (BIA), gait speed, and short physical performance battery (SPPB), while also discussing their inherent advantages and limitations. Such diagnostic advancements pave the way for early identification and unequivocal diagnosis of sarcopenia. Proceeding further, we provide a deep-dive into sarcopenia's pathogenesis, offering a thorough examination of associated signaling pathways like the Myostatin, AMP-activated protein kinase (AMPK), insulin/IGF-1 Signaling (IIS), and the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways. Each pathway's role in sarcopenia mediation is detailed, underscoring potential therapeutic target avenues. From a mechanistic perspective, the review also underscores the pivotal role of mitochondrial dysfunction in sarcopenia, emphasizing elements such as mitochondrial oxidative overload, mitochondrial biogenesis, and mitophagy, and highlighting their therapeutic significance. At last, we capture recent strides made in sarcopenia treatment, ranging from nutritional and exercise interventions to potential pharmacological and supplementation strategies. In sum, this review meticulously synthesizes the latest scientific developments in sarcopenia, aiming to enhance diagnostic precision in clinical practice and provide comprehensive insights into refined mechanistic targets and innovative therapeutic interventions, ultimately contributing to optimized patient care and advancements in the field.

Keywords:  AWGS; Aging; EWGSOP; Frailty; Mitochondrial dysfunction; Sarcopenia; Signaling pathway; Treatment coordination

DOI:  https://doi.org/10.1016/j.mam.2024.101270
Cureus. 2024 Mar;16(3): e55937

Successful Management of Chronic Wounds by an Autophagy-Activating Magnetized Water-Based Gel in Elderly Patients: A Case Series.

Piercarlo Minoretti, Manuel Gómez Serrano, Andrés Santiago Sáez, Miryam Liaño Riera, Ángel García Martín.

  Chronic wounds pose a significant threat to human health, particularly for the elderly, and require extensive healthcare resources globally. Autophagy, a key molecular player in wound healing, not only offers a defense against infections but also contributes to the deposition of the extracellular matrix during the proliferative phase. Additionally, it promotes the proliferation and differentiation of endothelial cells, fibroblasts, and keratinocytes. We have recently shown that applying magnetized saline water topically can trigger autophagy in intact skin. In this case series, we document the successful management of five non-infected, difficult-to-heal wounds in elderly patients using a topical autophagy-stimulating gel containing 95% magnetized saline water. The treated wounds included pressure ulcers, venous ulcers, and trauma-related injuries that had shown minimal or no improvement with standard wound therapies over a prolonged period. Application of the autophagy-stimulating gel promoted wound healing, as indicated by reduced fibrous and necrotic tissue, granulation tissue formation, re-epithelialization, and partial or complete wound closure. These preliminary case studies suggest that a topical gel containing magnetized saline water, which promotes autophagy, may aid healing of chronic wounds in elderly patients. Further investigation is warranted to explore the potential of this novel approach, as it may offer a valuable addition to the existing arsenal of wound care treatments for the aging population, particularly in addressing difficult-to-heal wounds.

Keywords:  autophagy; elderly; magnetized water; pressure ulcers; trauma-related injuries; venous ulcers; wound healing

DOI:  https://doi.org/10.7759/cureus.55937
Cancer Res. 2024 Apr 08. OF1-OF13

Integrin αvβ3 Upregulation in Response to Nutrient Stress Promotes Lung Cancer Cell Metabolic Plasticity.

Arin Nam, Shashi Jain, Chengsheng Wu, Alejandro Campos, Ryan M Shepard, Ziqi Yu, Joshua P Reddy, Tami Von Schalscha, Sara M Weis, Mark Onaitis, Hiromi I Wettersten, David A Cheresh.

Cancer stem/tumor-initiating cells display stress tolerance and metabolic flexibility to survive in a harsh environment with limited nutrient and oxygen availability. The molecular mechanisms underlying this phenomenon could provide targets to prevent metabolic adaptation and halt cancer progression. Here, we showed in cultured cells and live human surgical biopsies of non-small cell lung cancer that nutrient stress drives the expression of the epithelial cancer stem cell marker integrin αvβ3 via upregulation of the β3 subunit, resulting in a metabolic reprogramming cascade that allows tumor cells to thrive despite a nutrient-limiting environment. Although nutrient deprivation is known to promote acute, yet transient, activation of the stress sensor AMP-activated protein kinase (AMPK), stress-induced αvβ3 expression via Src activation unexpectedly led to secondary and sustained AMPK activation. This resulted in the nuclear localization of peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC1α) and upregulation of glutamine metabolism, the tricarboxylic acid cycle, and oxidative phosphorylation. Pharmacological or genetic targeting of this axis prevented lung cancer cells from evading the effects of nutrient stress, thereby blocking tumor initiation in mice following orthotopic implantation of lung cancer cells. These findings reveal a molecular pathway driven by nutrient stress that results in cancer stem cell reprogramming to promote metabolic flexibility and tumor initiation.
SIGNIFICANCE: Upregulation of integrin αvβ3, a cancer stem cell marker, in response to nutrient stress activates sustained AMPK/PGC1α signaling that induces metabolic reprogramming in lung cancer cells to support their survival. See related article by xxxx, p. xx.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-2700
Aging (Albany NY). 2024 Apr 04. 16

Evidence of a pan-tissue decline in stemness during human aging.

Gabriel Arantes Dos Santos, Gustavo Daniel Vega Magdaleno, João Pedro de Magalhães.

  Despite their biological importance, the role of stem cells in human aging remains to be elucidated. In this work, we applied a machine learning methodology to GTEx transcriptome data and assigned stemness scores to 17,382 healthy samples from 30 human tissues aged between 20 and 79 years. We found that ~60% of the studied tissues exhibit a significant negative correlation between the subject's age and stemness score. The only significant exception was the uterus, where we observed an increased stemness with age. Moreover, we observed that stemness is positively correlated with cell proliferation and negatively correlated with cellular senescence. Finally, we also observed a trend that hematopoietic stem cells derived from older individuals might have higher stemness scores. In conclusion, we assigned stemness scores to human samples and show evidence of a pan-tissue loss of stemness during human aging, which adds weight to the idea that stem cell deterioration may contribute to human aging.

Keywords:  longevity; senescence; stem cells; transcriptomics

DOI:  https://doi.org/10.18632/aging.205717
Sci Rep. 2024 Apr 11. 14(1): 8469

Mitochondrial Ca2+ signaling is a hallmark of specific adipose tissue-cancer crosstalk.

Agnese De Mario, Elisabetta Trevellin, Ilaria Piazza, Vincenzo Vindigni, Mirto Foletto, Rosario Rizzuto, Roberto Vettor, Cristina Mammucari.

Obesity is associated with increased risk and worse prognosis of many tumours including those of the breast and of the esophagus. Adipokines released from the peritumoural adipose tissue promote the metastatic potential of cancer cells, suggesting the existence of a crosstalk between the adipose tissue and the surrounding tumour. Mitochondrial Ca2+ signaling contributes to the progression of carcinoma of different origins. However, whether adipocyte-derived factors modulate mitochondrial Ca2+ signaling in tumours is unknown. Here, we show that conditioned media derived from adipose tissue cultures (ADCM) enriched in precursor cells impinge on mitochondrial Ca2+ homeostasis of target cells. Moreover, in modulating mitochondrial Ca2+ responses, a univocal crosstalk exists between visceral adipose tissue-derived preadipocytes and esophageal cancer cells, and between subcutaneous adipose tissue-derived preadipocytes and triple-negative breast cancer cells. An unbiased metabolomic analysis of ADCM identified creatine and creatinine for their ability to modulate mitochondrial Ca2+ uptake, migration and proliferation of esophageal and breast tumour cells, respectively.

DOI: https://doi.org/10.1038/s41598-024-55650-0
Mitochondrion. 2024 Apr 08. pii: S1567-7249(24)00035-7. [Epub ahead of print] 101877

Mrs2-mediated mitochondrial magnesium uptake is essential for the regulation of MCU-mediated mitochondrial Ca2+ uptake and viability.

Thiruvelselvan Ponnusamy, Prema Velusamy, Santhanam Shanmughapriya.

  Mitochondrial Ca2+ uptake is essential in regulating bioenergetics, cell death, and cytosolic Ca2+ transients. Mitochondrial Calcium Uniporter (MCU) mediates the mitochondrial Ca2+ uptake. Though MCU regulation by MICUs is unequivocally established, there needs to be more knowledge of whether divalent cations regulate MCU. Here, we set out to understand the mitochondrial matrix Mg2+-dependent regulation of MCU activity. We showed that decreased matrix [Mg2+] is associated with increased MCU activity and significantly prompted mitochondrial permeability transition pore opening. Our findings support the critical role of mMg2+ in regulating MCU activity.

Keywords:  Calcium; Cell death; MCU; Magnesium; Mitochondria; Mrs2; mPTP

DOI:  https://doi.org/10.1016/j.mito.2024.101877
bioRxiv. 2024 Mar 27. pii: 2024.03.24.584499. [Epub ahead of print]

An Innovative Mitochondrial-targeted Gene Therapy for Cancer Treatment.

Kai Chen, Patrick Ernst, Seulhee Kim, Yingnan Si, Tanvi Varadkar, Matthew D Ringel, Xiaoguang Margaret Liu, Lufang Zhou.

Targeting cancer cell mitochondria holds great therapeutic promise, yet current strategies to specifically and effectively destroy cancer mitochondria in vivo are limited. Here, we introduce mLumiOpto, an innovative mitochondrial-targeted luminoptogenetics gene therapy designed to directly disrupt the inner mitochondrial membrane (IMM) potential and induce cancer cell death. We synthesize a blue light-gated channelrhodopsin (CoChR) in the IMM and co-express a blue bioluminescence-emitting Nanoluciferase (NLuc) in the cytosol of the same cells. The mLumiOpto genes are selectively delivered to cancer cells in vivo by using adeno-associated virus (AAV) carrying a cancer-specific promoter or cancer-targeted monoclonal antibody-tagged exosome-associated AAV. Induction with NLuc luciferin elicits robust endogenous bioluminescence, which activates mitochondrial CoChR, triggering cancer cell IMM permeability disruption, mitochondrial damage, and subsequent cell death. Importantly, mLumiOpto demonstrates remarkable efficacy in reducing tumor burden and killing tumor cells in glioblastoma or triple-negative breast cancer xenografted mouse models. These findings establish mLumiOpto as a novel and promising therapeutic strategy by targeting cancer cell mitochondria in vivo .

DOI: https://doi.org/10.1101/2024.03.24.584499
Geroscience. 2024 Apr 12.

Differential mitochondrial bioenergetics and cellular resilience in astrocytes, hepatocytes, and fibroblasts from aging baboons.

Daniel A Adekunbi, Hillary F Huber, Cun Li, Peter W Nathanielsz, Laura A Cox, Adam B Salmon.

  Biological resilience, broadly defined as the ability to recover from an acute challenge and return to homeostasis, is of growing importance to the biology of aging. At the cellular level, there is variability across tissue types in resilience and these differences are likely to contribute to tissue aging rate disparities. However, there are challenges in addressing these cell-type differences at regional, tissue, and subject level. To address this question, we established primary cells from aged male and female baboons between 13.3 and 17.8 years spanning across different tissues, tissue regions, and cell types including (1) fibroblasts from skin and from the heart separated into the left ventricle (LV), right ventricle (RV), left atrium (LA), and right atrium (RA); (2) astrocytes from the prefrontal cortex and hippocampus; and (3) hepatocytes. Primary cells were characterized by their cell surface markers and their cellular respiration was assessed with Seahorse XFe96. Cellular resilience was assessed by modifying a live-cell imaging approach; we previously reported that monitors proliferation of dividing cells following response and recovery to oxidative (50 µM-H2O2), metabolic (1 mM-glucose), and proteostasis (0.1 µM-thapsigargin) stress. We noted significant differences even among similar cell types that are dependent on tissue source and the diversity in cellular response is stressor-specific. For example, astrocytes had a higher oxygen consumption rate and exhibited greater resilience to oxidative stress (OS) than both fibroblasts and hepatocytes. RV and RA fibroblasts were less resilient to OS compared with LV and LA, respectively. Skin fibroblasts were less impacted by proteostasis stress compared to astrocytes and cardiac fibroblasts. Future studies will test the functional relationship of these outcomes to the age and developmental status of donors as potential predictive markers.

Keywords:  Astrocytes; Baboons; Bioenergetics; Fibroblasts; Hepatocytes; Resilience

DOI:  https://doi.org/10.1007/s11357-024-01155-7
J Gerontol A Biol Sci Med Sci. 2024 Apr 12. pii: glae101. [Epub ahead of print]

Muscle mitochondrial bioenergetic capacities are associated with multimorbidity burden in older adults: the Study of Muscle, Mobility and Aging (SOMMA).

Theresa Mau, Terri L Blackwell, Peggy M Cawthon, Anthony J A Molina, Paul M Coen, Giovanna Distefano, Philip A Kramer, Sofhia V Ramos, Daniel E Forman, Bret H Goodpaster, Frederico G S Toledo, Kate A Duchowny, Lauren M Sparks, Anne B Newman, Stephen B Kritchevsky, Steven R Cummings.

   BACKGROUND: The geroscience hypothesis posits that aging biological processes contribute to many age-related deficits, including the accumulation of multiple chronic diseases. Though only one facet of mitochondrial function, declines in muscle mitochondrial bioenergetic capacities may contribute to this increased susceptibility to multimorbidity.
METHODS: The Study of Muscle, Mobility and Aging (SOMMA) assessed ex vivo muscle mitochondrial energetics in 764 older adults (mean age =76.4, 56.5% women, 85.9% non-Hispanic white) by high-resolution respirometry of permeabilized muscle fibers. We estimated the proportional odds ratio (POR [95%CI]) for the likelihood of greater multimorbidity (four levels: 0 conditions, N=332; 1 condition, N=299; 2 conditions, N=98; or 3+ conditions, N=35) from an index of 11 conditions, per SD decrement in muscle mitochondrial energetic parameters. Distribution of conditions allowed for testing the associations of maximal muscle energetics with some individual conditions.
RESULTS: Lower oxidative phosphorylation supported by fatty acids and/or complex-I and -II linked carbohydrates (e.g., Max OXPHOSCI+CII) was associated with a greater multimorbidity index score (POR=1.32[1.13,1.54]) and separately with diabetes mellitus (OR=1.62[1.26,2.09]), depressive symptoms (OR=1.45[1.04,2.00]) and possibly chronic kidney disease (OR=1.57[0.98,2.52]) but not significantly with other conditions (e.g., cardiac arrhythmia, chronic obstructive pulmonary disease).
CONCLUSIONS: Lower muscle mitochondrial bioenergetic capacities was associated with a worse composite multimorbidity index score. Our results suggest that decrements in muscle mitochondrial energetics may contribute to a greater global burden of disease and is more strongly related to some conditions than others.

Keywords:  aging muscle; energetics; geroscience; mitochondria; multimorbidity

DOI:  https://doi.org/10.1093/gerona/glae101