“The integration of artificial intelligence (AI), biomarkers, ageing biology, and longevity medicine stands as a cornerstone for extending human healthy lifespan.”
Imagine a future where we not only live longer but stay healthy throughout those extra years. Thanks to recent breakthroughs in biotechnology and artificial intelligence (AI) in healthcare, this vision is closer to becoming a reality.
Advancements in Aging Research
Aging research has made significant progress in recent years by combining disciplines like biology, technology, and medicine to tackle the challenges of extending healthspans and reducing age-related diseases. While people today live longer than ever before, extending our “healthspan”—the years we stay active and illness-free—remains challenging. AI and health biomarkers (biological indicators of our body’s condition) are now key tools in the pursuit of longer, healthier lives.
The work summarizes insights from the 2023 Aging Research and Drug Discovery Meeting. Researchers from renowned institutions explored how AI, biomarkers, and clinical applications can work together to enhance longevity. This fusion, termed “longevity biotechnology,” promises to transform healthcare from reactive treatments to proactive, preventive measures focused on staying healthy as we age.
The Challenge: Targeting Multiple Health Conditions with Longevity Biotechnology
Traditional aging research often targets single diseases, but most elderly individuals experience multiple chronic conditions. Addressing this complex challenge requires identifying biological markers that indicate aging and predicting health risks before diseases manifest.
The Breakthrough: AI in Biomarker Discovery for Aging
The study highlights how AI can accelerate the discovery of biomarkers, allowing scientists to understand aging at the cellular level. By using machine learning to identify unique patterns, researchers can estimate biological age, discover potential treatments, and evaluate the impact of lifestyle changes on health. This personalized approach enables healthcare providers to create prevention and treatment plans suited to each person’s unique health needs.
The Future of Healthcare: Preventive, AI-Driven Longevity Treatments
Currently, healthcare often focuses on managing diseases as they arise. However, these AI-driven tools could bring about a shift to preventive healthcare. Instead of waiting for age-related illnesses, clinicians could use AI insights to address aging’s root causes, improving health before issues arise.
While the promise of AI in healthcare is significant, the research team emphasizes that further investment is needed to make these AI-driven approaches accessible and accurate. With continued advancements, longevity biotechnology could become a standard part of healthcare, offering a new way to maintain vitality and well-being as we age.
Conclusion
Longevity biotechnology represents a groundbreaking shift, with AI and biomarkers helping us envision a future of healthier, longer lives. This approach brings us closer to understanding and managing the aging process, making extended healthspans a real possibility.
Click here to read the full research paper in Aging.
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Aging is indexed by PubMed/Medline (abbreviated as “Aging (Albany NY)”), PubMed Central, Web of Science: Science Citation Index Expanded (abbreviated as “Aging‐US” and listed in the Cell Biology and Geriatrics & Gerontology categories), Scopus (abbreviated as “Aging” and listed in the Cell Biology and Aging categories), Biological Abstracts, BIOSIS Previews, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).
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It is with great sadness and heavy heart that we announce the recent passing of Dr. Mikhail (Misha) V. Blagosklonny, our beloved Editor-in-Chief. Misha succumbed to metastatic lung cancer after a courageous battle.
Dr. Blagosklonny will be remembered as a brilliant and extraordinary scientist who dedicated his life to science. He was a visionary thinker, who made highly original contributions to cancer and aging research that were often ahead of their time.
Dr. Blagosklonny was born into a family of scientists. His mother, Professor of Medicine Yanina V. Blagosklonnaya, specialized in endocrinology and was a talented teacher, mentoring several generations of medical students. His father, Professor Vladimir M. Dilman, was a brilliant gerontologist, endocrinologist and oncologist, known for being a very charismatic person. He was the first person to encourage Misha to think about nature, aging, and philosophy.
Misha was a theorist by nature. While in school, he was deeply interested in physics and dreamed of becoming a theoretical physicist. Eventually, he chose biology, driven to study aging and age-related diseases, including cancer. He started as an experimentalist, but over the years, he became a theoretical biologist. In a way, his dream came true.
After earning his MD/PhD in cardiology and experimental medicine from Pavlov First State Medical University of St. Petersburg, Dr. Blagosklonny was awarded a prestigious Fogarty Fellowship from the National Institutes of Health (NIH) in Bethesda, MD. During his productive fellowship at the National Cancer Institute (NCI) in Dr. Leonard M. Neckers’s laboratory, he co-authored 18 publications in diverse areas of cancer research and was the last author on a clinical phase I/II trial paper. Then, he held a brief but productive senior research fellowship at the University of Pennsylvania in Dr. Wafik S El-Deiry’s laboratory before returning for several years to the NCI, where he collaborated with Dr. Tito Fojo. During those years, Dr. Blagosklonny co-authored over 30 research articles covering various topics in cancer research, including targeting HSP90, p53, Bcl2, Erb2, and Raf-1.
It was also at that time that, as a sole author, he published several experimental and theoretical papers encompassing the most important themes in his scientific career.
The first key theme focused on the selective protection of normal cells during cancer therapy. Despite the dogma, Dr. Blagosklonny showed that drug resistance provides opportunities for protection of non-resistant normal cells with selective killing of drug-resistant cancer cells. The original concept, titled “Drug-resistance enables selective killing of resistant leukemia cells: exploiting of drug resistance instead of reversal,” was published in Leukemia in 1999. The idea was so unconventional that, at first, it was incorrectly cited as “reversal of resistance” instead of “exploiting of resistance.”
Dr. Blagosklonny continued to develop the concept of normal cells protection in the following years. These are the most essential publications on this topic:
The second key theme was Dr. Blagosklonny’s innovative research method to generate new knowledge and ideas by synthesizing facts and observations from seemingly unrelated fields. This concept was published in Nature in 2002, titled “Conceptual biology: Unearthing the gems.”
The most significant outcome of this concept was the development of the hyperfunction (or quasi-programmed) theory of aging and the discovery of rapamycin as a potential anti-aging drug. Dr. Blagosklonny first published this idea in 2006, titled “Aging and immortality: quasi-programmed senescence and its pharmacologic inhibition.” Dr. Michael Hall, who discovered the protein TOR (Target of Rapamycin), credited Dr. Blagosklonny for “connecting dots that others don’t even see” in a Scientific American publication.
Dr. Blagosklonny held several faculty positions before joining Roswell Park Comprehensive Cancer Center as Professor of Oncology in 2009, and most recently served there as an adjunct faculty member. In his later years, Dr. Blagosklonny continued to develop his hyperfunction theory of aging and published extensively on the prevention of cellular senescence by rapamycin and other mTOR inhibitors, on cancer (an age-related disease) prevention by slowing down organismal aging, and on combinations of potential anti-aging drugs for use in humans.
These are just a few essential publications on those topics from more than 200 papers:
Dr. Blagosklonny has published more than 290 papers in peer-reviewed journals, serving as the first, last, or sole author on nearly all of his papers.
Dr. Blagosklonny was also a very passionate editor. He always dreamed of being an editor. It all began in 2002 when he was invited to become an Editor-in-Chief of the journalCell Cycle, a position he held for more than 16 years.
Understanding the importance of sharing scientific information without borders, he formulated the idea to launch journals for scientists, by scientists. Since cancer and aging research were always the main focus of his scientific interests, Dr. Blagosklonny, in collaboration with his colleagues, founded Aging in 2009 (co-editors-in-chief: the late Judith Campisi and David Sinclair) and Oncotarget in 2010 (co-editor-in-chief: Andrei Gudkov). Both journals are renowned for their outstanding Editorial Boards, innovative approaches, and significant popularity within the scientific community.
In 2012, Dr. Blagosklonny founded Oncoscience, a unique journal that publishes free of charge for both authors and readers. It can be considered a philanthropic endeavor.
In addition, Dr. Blagosklonny has served as an associate editor or a member of the editorial board of such journals as Cancer Research, International Journal of Cancer, Leukemia, Cell Death Differentiation, Cancer Biology & Therapy, American Journal of Pathology, Autophagy, and others.
Misha was a funny and witty person, who always had very interesting and unconventional opinions about various topics and was always looking for the roots of different matters. Everyone who knew him for a long time felt that they grew as a person because of his influence. He realized himself in this life as a scientist, editor, family man and a friend.
Dr. Blagosklonny envisioned his cancer battle as a mission to explore how metastatic cancer can be treated with curative intent. He published several articles about his battle, sharing original ideas and pushing the boundaries of cancer treatment in collaboration with his doctors. In his own words, Dr. Blagosklonny was near-curing of incurable cancer. He was in remission about two years and stayed active until the last days.
Dr. Blagosklonny passed away at his home in Boston, MA.
A special thank you to his colleagues and friends, who continuously supported Misha during his cancer battle: Dr. Tito Fojo, Dr. Wafik El-Deiry, Dr. Andrei Gudkov, Dr. Vadim Gladyshev and Dennis Mangan, to name a few.
Bone mass declines with age, and the anabolic effects of skeletal loading decrease. While much research has focused on gene transcription, how bone ages and loses its mechanoresponsiveness at the protein level remains unclear.
Researchers Christopher J. Chermside-Scabbo, John T. Shuster, Petra Erdmann-Gilmore, Eric Tycksen, Qiang Zhang, R. Reid Townsend, Matthew J. Silva from Washington University School of Medicine and Washington University in St. Louis, MO, share their findings which underscore the need for complementary protein-level assays in skeletal biology research.
In this study, the tibias of young-adult and old mice were analyzed using proteomics and RNA-seq techniques, while the femurs were examined for age-related changes in bone structure. A total of 1,903 proteins and 16,273 genes were detected through these analyses. Multidimensional scaling demonstrated a clear separation between the young-adult and old samples at both the protein and RNA levels. Furthermore, 93% of the detected proteins were also identifiable by RNA-seq, and the abundance of these shared targets showed a moderately positive correlation. Additionally, differential expression analysis revealed 183 age-related differentially expressed proteins and 2,290 differentially expressed genes between young-adult and old bone samples.
Proteomic and RNA-seq analyses were conducted on paired tibias from young-adult and old mice to study age-related differences and the effects of mechanical loading on bone formation. The results showed distinct differences in protein and gene expression between the two age groups. Many of the significantly upregulated and downregulated proteins and genes in old bone have been associated with bone phenotypes in genome-wide association studies (GWAS). The study also identified age-related differentially expressed proteins and genes involved in bone phenotypes and aging processes. Integrated analysis with GWAS data revealed eight targets that may be relevant to human disease, including Asrgl1 and Timp2. Furthermore, co-expression analysis identified an age-related module indicating baseline differences in TGF-beta and Wnt signaling. Baseline age-related differences in ECM/MMPs and TGF-beta signaling were detected in both the proteome and transcriptome. Following mechanical loading, the proteome showed distinct pathway, protein class, and process enrichments, with temporal differences observed between young-adult and old mice.
Overall, the findings provide valuable insights into the molecular mechanisms underlying age-related changes and the response to mechanical loading in mouse long bones.
DISCUSSION
This study aimed to compare the proteome and transcriptome of tibias from young-adult and old mice under baseline conditions and analyze changes in the bone proteome in response to mechanical loading. The researchers successfully developed a proteomics method to detect protein-level changes in cortical bone and used it to perform proteomic and RNA-seq analyses on tibias from both young-adult and old mice. They observed a moderately positive correlation between the proteome and transcriptome in bone tissue. Age-related differences were detected at both the protein and RNA levels, with altered TGF-beta signaling and changes in extracellular matrix (ECM) and matrix metalloproteinases (MMPs) protein and transcript levels in old bones. The researchers identified Tgfb2 as the most reduced Tgfb transcript in old bone, predominantly expressed by osteocytes. Proteomic analysis of the loading response showed modest changes compared to age-related differences, with fewer protein-level changes in old bones. The findings suggest that proteomics is a valuable tool for studying bone biology and can provide insights into protein-specific changes in aging.
The data obtained from the analysis were subjected to various statistical and data exploration techniques. Differential expression analysis was performed to compare protein abundance between different groups. Total RNA was extracted from the bones using TRIzol, and its integrity and concentration were measured. The bones were also processed for paraffin sectioning and RNA in situ hybridization.
Overall, the study involved the collection and analysis of bone samples from female mice to investigate age-related changes and loading responses in the skeletal system.
Click here to read the full research paper in Aging.
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Aging is indexed by PubMed/Medline (abbreviated as “Aging (Albany NY)”), PubMed Central, Web of Science: Science Citation Index Expanded (abbreviated as “Aging‐US” and listed in the Cell Biology and Geriatrics & Gerontology categories), Scopus (abbreviated as “Aging” and listed in the Cell Biology and Aging categories), Biological Abstracts, BIOSIS Previews, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).
Click here to subscribe to Aging publication updates.
“[…] our results suggest that sharing housing with others in early life might influence whole-life attributes, potentially leading to specific life history traits beyond the typical relationship between the growth rate and lifespan.”
A study on African turquoise killifish examined the impact of housing density on juvenile growth. Newly hatched fish were kept in different densities ranging from 1 to 40 fish per tank. It was found that lower housing densities resulted in faster growth, with fish in single housing growing significantly larger than those in group housing. Additionally, single-housed fish reached sexual maturity earlier compared to group-housed fish at higher densities. Comparisons between group-housed and single-housed fish showed that housing conditions in the juvenile stage did not affect the appearance changes during sexual maturation.
As the fish progressed to middle-aged adults, the rate of increase in body length slowed down, while body weight continued to increase. Differences in body weight between group-housed and single-housed fish persisted into old age, suggesting potential differences in body composition. Surprisingly, single-housed fish had a longer mean adult lifespan compared to group-housed fish, contradicting the commonly held belief that faster growth leads to shorter lifespan. Lower housing densities during the juvenile stage were also found to extend adult lifespan, further challenging the inverse correlation between growth rate and lifespan. These findings suggest that lower housing densities promote accelerated growth in the juvenile stage of African turquoise killifish.
The study also found that single-housed fish had a longer adult lifespan compared to group-housed fish. This led to the suspicion that the egg-laying period of single-housed fish might also be longer. To investigate this, the researchers conducted weekly monitoring of the number of eggs laid until the old adult stage. In group-housed fish, the number of eggs laid was high for the first two weeks, followed by a medium level for the subsequent five weeks, and then decreased. In contrast, single-housed fish showed a medium level of egg-laying for the first nine weeks, followed by a decrease. The cumulative number of live embryos was found to be lower in single-housed fish compared to group-housed fish. These findings suggest that while the number of eggs laid is not very high, single-housed fish have a longer egg-laying period than group-housed fish.
To investigate the potential reasons behind the reduction in offspring number and longer egg-laying period in single-housed fish, the researchers conducted RNA sequencing analysis of testes or ovaries at four life stages. These stages included the onset of sexual maturity, young adult, mature adult, and middle-aged adult. Interestingly, the analysis revealed that single-housed fish showed higher similarity to group-housed fish at earlier life stages compared to group-housed fish at the same life stage. For instance, in the testes, single-housed fish at stage II exhibited the highest similarity to group-housed fish at stage I. Similarly, in the ovaries, single-housed fish at stage II and III showed higher similarity to group-housed fish at stage I. These findings suggest that the rate of gonadal transcriptional change with life stage progression is slower in single-housed fish compared to group-housed fish.
The researchers identified differentially expressed genes (DEGs) between stage I and stage IV in group- and single-housed fish. In the testes, ribosome-related genes and cilium-related genes were highly enriched in DEGs with higher expression in stage I compared to stage IV, suggesting a link between life stage progression, testes development, and spermatogenesis. In the ovaries, growth-related genes and translation-related genes were highly enriched in DEGs with higher expression in stage I compared to stage IV, indicating a link between life stage progression, ovarian development, oogenesis, and aging. Comparing group-housed and single-housed fish at different stages, there were differences in the PC1 values, suggesting that single-housed fish exhibited slower progression of gametogenesis and gonadal maturation relative to life stage progression compared to group-housed fish.
To further investigate this, the researchers focused on specific genes related to spermatogenic differentiation, oocyte development, oocyte construction, and female gonad development. The expression of these genes showed slower changes with life stage progression in single-housed fish compared to group-housed fish in both the testes and ovaries. This suggests that single-housed fish may have slower rates of gametogenesis and gonadal maturation, leading to a lower proportion of mature sperm and oocytes in their gonads. Overall, the results indicate that, at the transcriptional level, the progression of gonadal maturation and ovarian aging is slower in single-housed fish compared to group-housed fish. This slower progression may explain the medium fecundity and extended egg-laying period observed in single-housed fish.
The liver was chosen for analysis as it plays a central role in organismal metabolic processes. Gene expression profiles of the livers were compared between group- and single-housed fish at two different ages: 7 weeks post-hatching (wph) and 14 wph. Surprisingly, despite the 2-week age difference, the correlation coefficients showed that group- and single-housed fish at 14 wph were highly similar. The researchers identified 1588 age-related differentially expressed genes (DEGs) between the two age groups. Hierarchical clustering based on the expression changes of these age-related genes demonstrated that the expression profiles of group- and single-housed fish were similar at 14 wph.
IN CONCLUSION
In summary, juvenile single housing in African turquoise killifish promotes faster growth, longer egg-laying periods, and extended lifespans compared to group housing. These findings challenge traditional assumptions about the relationship between growth and lifespan and shed light on the impact of early-life environmental conditions on overall life history.
Overall, the experiments involved maintaining and rearing the fish, measuring their body length and weight, analyzing RNA sequencing data, measuring lifespan, and counting the number of eggs laid. Statistical analysis was conducted to assess significant differences between groups.
Click here to read the full research paper in Aging.
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Aging is indexed by PubMed/Medline (abbreviated as “Aging (Albany NY)”), PubMed Central, Web of Science: Science Citation Index Expanded (abbreviated as “Aging‐US” and listed in the Cell Biology and Geriatrics & Gerontology categories), Scopus (abbreviated as “Aging” and listed in the Cell Biology and Aging categories), Biological Abstracts, BIOSIS Previews, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).
Click here to subscribe to Aging publication updates.
Researchers introduce SINGULAR, a cell rejuvenation atlas that provides a unified analysis framework to study the effects of rejuvenation strategies at the single-cell level.
Various strategies, including lifestyle changes, gene therapies, and surgical procedures, have shown promise in improving aging markers and increasing lifespan in model organisms. These interventions often have limitations, however, such as not achieving comprehensive functional improvement across tissues or facing challenges in clinical translation. To address these limitations, the researchers characterized and compared rejuvenation interventions at different biological levels. The paper introduces SINGULAR, a cell rejuvenation atlas that provides a unified analysis framework to study the effects of rejuvenation strategies at the single-cell level. By examining gene regulatory networks, intracellular signaling, cell-cell communication, and cellular processes, the atlas identifies master regulators and common targets across immune cells. SINGULAR has the potential to inform future advancements in human age reversal and aid in the selection of drugs that mimic the effects of rejuvenation interventions.
RESULTS
The authors propose a unified multiscale analysis pipeline for characterizing and comparing the effects of rejuvenation interventions. This process begins by filtering low-quality cells, normalizing expression profiles, and identifying optimal cell clustering. The data is then analyzed at various biological levels, including differential gene expression, transcriptional regulatory networks, signaling cascades, and intercellular communication.
Nine previously published single-cell RNA-seq datasets from different rejuvenation interventions were collected and analyzed, revealing technical variability that highlights the need for a standardized data processing pipeline. The analysis showed heterogeneous gene expression responses across different cell types and organs. Systemic interventions had consistent effects on multiple organs, while metformin had minimal impact. Interestingly, exercise produced the largest transcriptional effects in the liver, artery, and spinal cord, even though it primarily targets muscles.
Transcriptional regulatory networks (TRNs) were reconstructed to explore the regulatory mechanisms behind these gene expression changes. The TRNs, which averaged 72 genes, were highly hierarchical, indicating the presence of ‘master regulators’ that explain significant portions of gene expression changes.
To demonstrate the practical application of SINGULAR, the study investigated the identification of drugs that could target transcription factor (TF) master regulators and key signaling molecules. Drug-target relationships from DrugBank were analyzed to find drugs that could activate master regulators or mimic the effects of rejuvenation interventions. Interestingly, only 17 out of 239 TFs could be activated by drugs, primarily nuclear receptors, with notable exceptions like AP-1 complex proteins and Trp53. Some of these drugs, such as Curcumin and Vitamin D3, have shown rejuvenating effects on lifespan in model organisms. Key signaling molecules were found to be more druggable, with several drugs targeting specific molecules, though none targeted both genes.
The study aimed to identify master regulators and their downstream effects in rejuvenation interventions. By simulating the activation of transcription factors (TFs) within the network, the researchers quantified the number of genes regulated by each TF. They discovered 493 TFs with non-zero activity across various conditions, though most acted as master regulators in only a few cases. The study also highlighted key differences between TFs involved in aging-related activity changes and those regulating rejuvenation. Notably, the AP-1 complex, consisting of Fos and Jun, emerged as a common master regulator across multiple interventions. The researchers also identified TFs linked to aging and validated their potential rejuvenating effects experimentally. They also explored crosstalk between TFs and signaling pathways, finding negative enrichment of aging gene sets in several integrated networks. Overall, the findings offer valuable insights into the regulatory mechanisms and potential rejuvenating effects of master regulators and signaling molecules involved in rejuvenation interventions.
CONCLUSION
In conclusion, this study employed a unified analysis pipeline, SINGULAR, to compare the effects and mediators of various rejuvenation interventions. Key master regulators, including Arntl, AP-1 complex proteins, NFE2L2, and MAF, were identified as playing crucial roles in rejuvenation. The analysis revealed distinct differences between aging-related transcriptional changes and rejuvenation regulators. Immune and skin cell types were highlighted as potential intervention targets, with the possibility of additive or synergistic effects by targeting non-overlapping master regulators. Some limitations were noted, such as biases in cell type comparisons, reliance on ligand-receptor interactions for cell-cell communication analysis, and the risk of false negatives in differential expression testing. Despite these limitations, SINGULAR offers valuable insights into rejuvenation mechanisms and the identification of agents for anti-aging strategies. It provides a robust framework for understanding the mechanisms behind various interventions and offers a wide range of potential target genes for a comprehensive anti-aging approach.
Click here to read the full research paper in Aging.
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Aging is indexed by PubMed/Medline (abbreviated as “Aging (Albany NY)”), PubMed Central, Web of Science: Science Citation Index Expanded (abbreviated as “Aging‐US” and listed in the Cell Biology and Geriatrics & Gerontology categories), Scopus (abbreviated as “Aging” and listed in the Cell Biology and Aging categories), Biological Abstracts, BIOSIS Previews, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).
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In this study, researchers reinforce knowledge about an age-related alteration in the synthesis of major proteins linked to the migratory and contractile functions of dermal human fibroblasts.
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Dermal fibroblasts orchestrate the synthesis and degradation of extracellular matrix components, which is crucial for skin homeostasis. Alterations in the expression of components such as collagens and enzymes can lead to reduced mechanical cutaneous tension and impaired skin wound healing during aging.
Researchers Françoise Boismal, Sandy Peltier, Sophie Ly ka so, Guillaume Chevreux, Loïse Blondel, Kévin Serror, Niclas Setterblab, Elina Zuelgaray, David Boccara, Maurice Mimoun, Christelle Guere, Armand Benssussan, Marie Dorr, Gallic Beauchef, Katell Vie, and Laurence Michel from Saint-Louis Hospital, Paris; Paris University, Paris Cité; Jacques-Monod Institute, Paris; and Clarins Laboratories, Pontoise, aimed to better understand the molecular alterations in fibroblasts during aging by comparing secretomic and proteomic signatures of fibroblasts from young (<35years) and aged (>55years) skin donors, in quiescence or TGF-stimulated conditions, using HLPC/MS.
Dermal fibroblasts were obtained from healthy, sun-protected skin of young (<35 years) and aged (>55 years) healthy women undergoing breast reduction surgery. Peptides were loaded using an online preconcentration method and separated by chromatography. RNA extraction, reverse transcription, quantitative PCR, and blot quantification were performed, along with immunostaining on fibroblasts seeded on culture chamber slides.
To identify key molecules involved in the role of human dermal fibroblasts during wound healing and skin aging, a comparative analysis of the secretome and proteome of 12 fibroblast cultures, freshly isolated from young and mature skin, was conducted using HPLC/MS. This analysis was performed in both quiescence and TGF-β1-treated conditions, without senescence-inducing factors, as described in previously reported aging models. Importantly, the analyses were conducted in the absence of serum in the culture medium 24 hours before and during cell stimulation to avoid serum protein contamination in the secretomic and proteomic assays
This study revealed a significant decrease in fibroblast protein secretion with age, while cytoplasmic protein accumulation increased by over 60%. Proteins related to actin and ECM (extracellular matrix) organization were the two main categories altered during aging. An in-depth analysis of actin-related proteins highlighted the involvement of CFL1, CORO1C, the ARP2/3 complex, FLNB, and ACTC1 in cytoskeleton organization and fibroblast migration. These findings offer potential new targets to slow key features of skin aging.
“Our present data reinforce knowledge about an age-related alteration in the synthesis of major proteins linked to the migratory and contractile functions of dermal human fibroblasts.” Read the full research paper, published in Aging.
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Aging is an open-access, traditional, peer-reviewed journal that publishes high-impact papers in all fields of aging research. All papers are available to readers (at no cost and free of subscription barriers) in bi-monthly issues at Aging-US.com.
Click here to subscribe to Aging publication updates.
Cell death is a fundamental process essential to various biological phenomena, including development, tissue homeostasis, and immune responses. There are several distinct pathways of cell death, each with unique characteristics and implications for host immunological pathways.
Apoptosis: The earliest discovered form of programmed cell death, apoptosis is a tightly regulated process controlled by genetic machinery, playing a crucial role during embryonic development to eliminate unwanted cells.
Autophagy: Often referred to as type 2 cell death, autophagy is a conserved cellular process that degrades unwanted or damaged organelles, acting as a recycling mechanism to maintain cellular metabolism, particularly during starvation or cellular stress.
Pyroptosis: Triggered by the activation of the inflammasome complex, pyroptosis is associated with the rapid clearance of intracellular pathogens, particularly in immune cells, keratinocytes, and epithelial cells. It induces the release of pro-inflammatory cytokines like interleukin-1β and interleukin-18.
Ferroptosis: Characterized by the accumulation of lipid peroxides due to excess intracellular iron, ferroptosis disrupts membranes through lipid peroxidation, contributing to the elimination of intracellular microorganisms.
Necroptosis: A programmed form of cell death distinct from necrosis, necroptosis is mediated by receptor-interacting protein kinases and is associated with macrophage death, inducing pro-inflammatory immune responses and the release of damage-associated molecular patterns.
NETosis: A unique form of cell death involving neutrophils, NETosis results in the release of neutrophil extracellular traps (NETs), networks of DNA and proteins that capture and kill extracellular microorganisms. This pathway is associated with the TH17 immunological pathway and regulated by cytokines like interleukin-17.
These cell death pathways are closely interconnected with host immunological pathways, playing crucial roles in the defense against various pathogens. Understanding these interactions provides valuable insights into the complex relationship between cell death and immune responses.
Conclusion
Programmed cell death pathways are intimately linked with host immunological responses, offering insights into the host’s defense mechanisms against pathogens. This understanding can pave the way for developing better therapeutic strategies against infections and autoimmune disorders.
“The intricate network of host immunological pathways, categorized into eradicable and tolerable immune responses, showcases the remarkable adaptability and specificity of the immune system in combating diverse pathogens.” Click here to read the full review in Aging.
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Aging is an open-access, traditional, peer-reviewed journal that publishes high-impact papers in all fields of aging research. All papers are available to readers (at no cost and free of subscription barriers) in bi-monthly issues at Aging-US.com.
Click here to subscribe to Aging publication updates.
In a new study, researchers investigated myocyte-secreted factors with the potential to suppress cellular senescence, aiming to explore their protective effects against lung disease.
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Over the human lifespan, our cells encounter numerous stressors that can trigger an intrinsic defense mechanism called cellular senescence. Cellular senescence is characterized by irreversible growth arrest and can act as a safeguard against cancer. However, when senescent cells accumulate in various tissues as we age, it can contribute to tissue degeneration and chronic diseases.
The senescence-associated secretory phenotype (SASP), a hallmark of senescent cells, plays a critical role by secreting inflammatory factors, proteases, and growth factors, disrupting tissue balance and fueling pathological conditions. Consequently, selectively eliminating senescent cells has emerged as a promising therapeutic strategy, potentially restoring tissue function and mitigating age-related disorders.
COPD: Chronic Obstructive Pulmonary Disease
Chronic obstructive pulmonary disease (COPD) exemplifies the impact of cellular senescence on health, characterized by the collapse of alveolar walls in the lungs. Accelerated accumulation of senescent cells in COPD patients’ lung tissues links senescence to the disease’s pathogenesis. Genetic or pharmacological elimination of these cells in preclinical models has shown significant reductions in emphysema-associated pathologies and restoration of pulmonary function, highlighting the potential of senolytic therapies.
Regular physical activity offers benefits beyond fitness, including cardiovascular and mental well-being enhancements, and modulates cellular senescence. Studies show an association between habitual exercise and lower levels of senescence markers in various tissues. Researchers have focused on myokines, signaling factors secreted by skeletal muscles in response to exercise, as potential mediators of these benefits. Irisin, a myokine, has shown promise in suppressing cellular senescence and correlating inversely with COPD severity.
In this recent study, pigment epithelium-derived factor (PEDF) emerged as a key player in the interplay between exercise, cellular senescence, and lung pathologies. Initially known for its role in retinal development, PEDF has been linked to cellular senescence modulation, extending the replicative lifespan of fibroblasts and diminishing senescence markers. PEDF mitigates oxidative stress by reducing reactive oxygen species levels and modulates microRNAs, particularly miR-127, implicated in cellular senescence.
“We found that myocyte-derived factors significantly extended the replicative lifespan of fibroblasts, suggesting that myokines mediate the anti-senescence effects of exercise.”
Exercise significantly upregulates PEDF expression in skeletal muscles, correlating with reduced senescence markers and SASP-related genes in the lungs. Recombinant PEDF administration in mice has shown remarkable results, reducing senescence markers and preserving alveolar structure in pulmonary emphysema models, translating into improved pulmonary function. While some preclinical evidence supports PEDF’s therapeutic potential, translating these findings to clinical applications requires rigorous safety and efficacy evaluations. Understanding PEDF’s signaling pathways could unveil new therapeutic targets, and its potential involvement in other age-related disorders warrants further investigation. The interplay between PEDF and other exercise-induced factors offers potential for novel therapeutic strategies.
“Collectively, these results strongly suggest that PEDF contributes to the beneficial effects of exercise, potentially suppressing cellular senescence and its associated pathologies.”
Conclusions
The discovery of PEDF’s role in exercise-induced senescence suppression and its therapeutic potential in lung pathologies represents a paradigm shift in senescence research. Understanding the interplay between physical activity, myokine signaling, and senescence modulation can lead to targeted interventions promoting healthy aging. Multidisciplinary collaborations are essential to harness the potential of PEDF and other senescence-modulating factors, paving the way for innovative treatments that alleviate age-related diseases and improve quality of life.
Aging is an open-access, traditional, peer-reviewed journal that publishes high-impact papers in all fields of aging research. All papers are available to readers (at no cost and free of subscription barriers) in bi-monthly issues at Aging-US.com.
Click here to subscribe to Aging publication updates.
In this new study, researchers investigated the intricate link between mitophagy and cancer stem cells.
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Cellular quality control mechanisms like mitophagy, a specialized form of autophagy that eliminates dysfunctional mitochondria, play a pivotal role in various physiological processes. Defects in mitophagy have been linked to neurodegeneration, heart failure, cancer, and aging.
A recent study, by researchers Marta Mauro-Lizcano, Federica Sotgia, and Michael P. Lisanti from the University of Salford, has shed light on the intricate link between mitophagy and cancer stem cells (CSCs). In this study, the researchers developed an innovative fluorescence-based approach to enrich subpopulations of cancer cells exhibiting high basal levels of mitophagy. Their findings reveal that elevated mitophagy activity enhances CSC properties, including self-renewal, ATP production, proliferation, and cell migration, underscoring the potential of targeting mitophagy as a therapeutic strategy for cancer treatment.
“CSCs are responsible for cancer relapse, therapy-resistance, and metastatic dissemination. Therefore, CSC elimination is necessary to prevent cancer recurrence and improve long-term patient outcomes. The search of new targets against CSCs is essential for the success of cancer treatment.” — Mauro-Lizcano et al.
Background
Mitophagy plays a crucial role in maintaining cellular homeostasis by selectively degrading damaged or superfluous mitochondria. This process is governed by specific mitochondrial outer membrane receptors, such as BNIP3 and BNIP3L (also known as NIX), which interact with autophagy-related proteins like LC3/GABARAP to initiate mitophagy. The current study focused on the BNIP3/BNIP3L-dependent pathway, which is rapidly induced under cellular stress conditions like hypoxia and nutrient deprivation.
Cancer stem cells (CSCs) are a subpopulation of cells within a tumor that exhibit stem cell-like properties, such as self-renewal, tumor initiation capability, and drug resistance. These cells are implicated in cancer recurrence, treatment failure, and metastatic dissemination, making their elimination a critical target for effective cancer therapy. Accumulating evidence suggests that mitophagy plays a pivotal role in sustaining CSC properties, including self-renewal, cell propagation, and tumorigenic ability. Consequently, targeting mitophagy has emerged as a promising approach for CSC eradication.
The Study
To investigate the role of mitophagy in CSCs, the researchers developed a novel model system to enrich subpopulations of cancer cells with high basal levels of mitophagy. They employed a BNIP3(L)-promoter-eGFP-reporter system, where the transcriptional activity of BNIP3 and BNIP3L was linked to the expression of enhanced green fluorescent protein (eGFP). This allowed the isolation of cancer cells with high BNIP3/BNIP3L transcriptional activity, indicative of elevated mitophagy levels, using flow cytometry.
The validity of the model was confirmed through various functional assays. Immunoblotting revealed higher protein levels of BNIP3 and BNIP3L in the eGFP-high subpopulations. Additionally, these cells exhibited increased lysosomal mass and mitophagy activity, as measured by flow cytometry using specific probes. Furthermore, the researchers employed the mitochondrially-targeted red fluorescent protein (mt-Keima) to directly visualize and quantify mitophagy, providing further evidence of the model’s robustness.
“Mammospheres, or mammary epithelial stem cell aggregates, derived from primary breast tumors or cell lines are thought to develop from rare cancer stem cell (CSC) subpopulations within the tumor.” — Millipore Sigma
To investigate the role of mitophagy in CSC propagation, the researchers compared the mammosphere-forming ability, a functional assay for anchorage-independent growth and self-renewal, between eGFP-high and eGFP-low subpopulations. The eGFP-high cells demonstrated a statistically significant increase in mammosphere formation, indicating enhanced CSC properties. Moreover, these cells exhibited higher levels of CD44, a well-known cell surface marker of CSCs.
To further validate the mammosphere phenotype’s dependence on mitophagy, the researchers treated the eGFP-high and eGFP-low cells with chloroquine, an autophagy inhibitor, and cyclosporin A, a specific mitophagy inhibitor. Interestingly, the eGFP-low subpopulations were more sensitive to both inhibitors, suggesting that the high levels of endogenous mitophagy in the eGFP-high cells conferred resistance to these agents, further reinforcing the functional implication of mitophagy in mammosphere formation.
ATP Production & Mitochondrial Activity
To better understand the effects of mitophagy on CSCs, the researchers analyzed their metabolic profiles. The eGFP-high cells exhibited significantly higher ATP levels compared to eGFP-low cells, despite similar mitochondrial mass. Notably, the eGFP-high cells also demonstrated an increased GSH/GSSG ratio, indicating higher antioxidant capacity and better mitochondrial function.
Proliferation & Cell Cycle Progression
Cell cycle analysis revealed that the eGFP-high cells exhibited a decreased G0/G1 phase and corresponding increases in the S and G2/M phases, suggesting a more proliferative phenotype. This finding aligns with the observed increase in ATP production and mitochondrial activity, supporting the notion that mitophagy contributes to the energetic and proliferative advantages of CSCs.
Drug Resistance: Tamoxifen & Palbociclib
To assess the potential drug resistance phenotype of the eGFP-high and eGFP-low subpopulations, the researchers evaluated their sensitivity to 4-OH-Tamoxifen, an FDA-approved drug for treating estrogen receptor-positive (ER+) breast cancer, and Palbociclib, a CDK4/6 inhibitor. Remarkably, the eGFP-high cells exhibited multi-drug resistance, with significantly higher mammosphere formation compared to the eGFP-low cells upon treatment with these agents, further underscoring the aggressive nature of mitophagy-high CSCs.
Cell Migration and Metastatic Potential
Using the highly metastatic MDA-MB-231 breast cancer cell line, the researchers investigated the migratory capacity of the eGFP-high and eGFP-low subpopulations. Consistent with the observed stemness and metabolic advantages, the eGFP-high MDA-MB-231 cells exhibited higher levels of cell migration, suggesting that elevated mitophagy contributes to the metastatic potential of CSCs.
Therapeutic Implications & Future Directions
“In summary, our current work has provided a novel strategy to enrich for a sub-population of cancer cells, with high basal levels of mitophagy.” — Mauro-Lizcano et al.
The findings of this study highlight the critical role of mitophagy in driving various hallmarks of CSCs, including self-renewal, ATP production, proliferation, and cell migration. By targeting mitophagy, particularly the BNIP3/BNIP3L-dependent pathway, researchers may be able to develop novel therapeutic strategies for eliminating CSCs and improving patient outcomes in cancer treatment.
Future research should focus on exploring the molecular mechanisms underlying the observed effects of mitophagy on CSC properties and identifying specific mitophagy inhibitors or modulators with potential therapeutic applications. Additionally, further investigation into the interplay between mitophagy and other cellular processes, such as metabolic reprogramming and signaling pathways, could provide valuable insights into the complex biology of CSCs and pave the way for more effective targeted therapies.
Conclusion
The study by Mauro-Lizcano et al. represents a significant advancement in our understanding of the role of mitophagy in cancer stem cell biology. By developing an innovative model system and employing a multifaceted approach, the researchers have unveiled the energetic drivers and functional implications of mitophagy in stemness features, ATP production, proliferation, and cell migration. These findings not only deepen our knowledge of the intricate mechanisms governing CSC behavior but also highlight the potential of targeting mitophagy as a promising therapeutic strategy for combating cancer recurrence, treatment resistance, and metastatic dissemination.
Click here to read the full research paper published in Aging.
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Aging is an open-access, traditional, peer-reviewed journal that publishes high-impact papers in all fields of aging research. All papers are available to readers (at no cost and free of subscription barriers) in bi-monthly issues at Aging-US.com.
Click here to subscribe to Aging publication updates.
In this new study, researchers used proteomics to investigate Werner syndrome and proteins associated with age and/or genotype in the serum and liver of mice.
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Werner syndrome (WS) is a rare genetic disorder marked by the premature onset of features typically associated with normal aging. This autosomal recessive condition manifests in individuals who generally develop normally until adolescence. As the syndrome progresses, affected individuals are predisposed to age-related diseases much earlier in life. These conditions include cataracts, type 2 diabetes, atherosclerosis, osteoporosis, and various cancers. The underlying cause of Werner syndrome is believed to be mutations in the WRN gene, which encodes a RecQ helicase crucial for DNA repair and replication.
Despite the accelerated aging, cognitive function remains unaffected in individuals with WS, providing a unique model for studying the mechanisms of aging and exploring potential therapeutic interventions. Although extensive research has been conducted, the precise mechanisms underlying these effects remain elusive.
“Proteomics analysis at different ages allows us to follow the progressive biological alterations (including histological fat accumulation) in the liver according to age and/or the Wrn genotype.”
Key Findings: Sexual Dimorphism & Immune Response
“The major goal of this study was to look at murine hepatic proteomic profiles at two different time points and determine the impact of a mutation in the Wrn gene product with age in the liver of mice.”
The study’s most compelling discovery was the significant sexual dimorphism in liver tissue and serum proteome profiles, regardless of age or genotype. Principal component analysis (PCA) revealed distinct clustering patterns, indicating fundamental differences in protein expression between male and female mice. This highlights the importance of considering sex in biomedical research due to its potential impact on disease progression and treatment responses.
Additionally, the research unveiled an enrichment of proteins involved in immune responses, particularly in the liver tissue of WRN mutant mice. Elevated levels of specific immunoglobulin variants (Igkc, Ighm, and Igkv5-39) in aged WRN mutant mice suggest a link to fatty liver progression in WS. Both sexes exhibited fatty liver; however, aged male WRN mutant mice showed significant upregulation of proteins involved in lipid and fatty acid metabolism, exacerbating age-related fat accumulation in the liver. Increased proteins related to oxidant detoxification processes in male WRN mutant mice indicated a heightened cellular antioxidant response, aligning with oxidative stress’s role in aging.
Implications & Future Directions
Several proteins altered in aged WRN mutant mice, such as A1bg, Vnn1, and Serpina1e, have been linked to chronic liver diseases in humans, emerging as potential biomarkers for disease progression. These findings offer insights for future diagnostic and therapeutic strategies. The study’s robust experimental design and rigorous analytical approaches, including label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS), PCA, hierarchical clustering, and gene ontology enrichment analyses, lend credibility to its findings.
Future research should address limitations such as broader age ranges, tissue specificity, and functional validation to build on these findings. The study underscores the importance of considering sex in biomedical research and opens new avenues for exploring protein alterations as biomarkers or therapeutic targets, potentially improving diagnosis, disease monitoring, and personalized treatment strategies for WS and related age-associated disorders.
Click here to read the full research paper published in Aging.
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Aging is an open-access, traditional, peer-reviewed journal that publishes high-impact papers in all fields of aging research. All papers are available to readers (at no cost and free of subscription barriers) in bi-monthly issues at Aging-US.com.
Click here to subscribe to Aging publication updates.
