Understanding Genetic Influences on Aging

Oxidative Stress, Mitochondria, and Lifespan: OSER1's Multifaceted Impact on Aging This article presents groundbreaking research on a newly identified protein called OSER1 (Oxidative stress-responsive serine-rich protein 1) that regulates lifespan and stress resistance across multiple species. The study, published in August 2024, used a comprehensive approach, employing silkworms, nematodes (C. elegans), fruit flies (D. melanogaster), and human cells to investigate OSER1's functions and mechanisms. The researchers discovered that OSER1 is a direct target of FOXO transcription factors known to modulate aging-related pathways. Through various experiments, they found that overexpression of OSER1 extended lifespan in silkworms, nematodes, and flies, while its depletion shortened lifespan. OSER1 plays a critical role in protecting against oxidative stress, with organisms overexpressing OSER1 demonstrating increased resistance to oxidative damage, starvation, and heat shock. At the cellular level, OSER1 regulates mitochondrial function and morphology. In C. elegans, the knockdown of OSER1 led to fragmented mitochondria and decreased ATP production. The protein also appeared to influence reproduction, with its overexpression increasing fertility in silkworms and nematodes. The study extended its findings to humans, where genetic variants of OSER1 were associated with longevity in a cohort of individuals over 90 years old. Proteomic analysis in human cells suggested that OSER1 is involved in cellular senescence, cell cycle regulation, and oxidative stress response. This research identifies OSER1 as a conserved longevity and stress resistance regulator, acting downstream of the FOXO signaling pathway. The discovery of OSER1's role in aging and stress response opens up new avenues for understanding the biology of aging and potentially developing interventions to promote healthy aging across species, including humans. This article is crucial in anti-aging medicine as it unveils OSER1 as a novel, evolutionarily conserved regulator of lifespan and stress resistance. The study's importance lies in its comprehensive approach, demonstrating OSER1's role across multiple species and linking it to established aging pathways like FOXO signaling. OSER1's involvement in protecting against oxidative stress and maintaining mitochondrial function addresses key aspects of aging biology. The discovery of OSER1 genetic variants associated with human longevity provides direct relevance to human aging, bridging the gap between animal studies and human biology. This multifaceted protein influences stress resistance, mitochondrial function, and reproduction, highlighting the interconnected nature of aging processes. The potential to modulate lifespan and stress resistance by altering OSER1 expression opens up new possibilities for anti-aging interventions. JP https://lnkd.in/ee5uwNzT

🧬 Cracking the Longevity Code: How Acetylation Sites Shape Mammalian Lifespan 🔍 Why do some mammals live decades longer than others? A new study in Nature Magazine Communications proposes a molecular answer — a hidden layer of regulation: protein acetylation patterns in the acetylome. To address this, the authors from Bar-Ilan University developed PHARAOH, a novel computational tool that analyzes post-translational modifications (PTMs) across 107 mammalian species with 100-fold differences in longevity. PHARAOH uncovered over 1,000 lysine acetylation sites whose conservation, replacement, or gain is significantly associated with lifespan extension. Acetylation is the reversible addition of an acetyl group (–COCH₃) to lysine residues, modifying protein function in response to cellular conditions. 🧠 Key enriched pathways among longevity-associated acetylation sites: -One-carbon metabolism and transsulfuration -Mitochondrial translation and oxidative phosphorylation -Fatty acid oxidation and PPAR signaling -DNA repair (non-homologous end joining, mismatch repair) -Cell cycle regulation -Oxidative stress response These pathways align with known hallmarks of aging. Specific acetylation states at key residues were linked to survival advantages across species. 🧪 Mechanistic validation: turning correlation into causation Unlike many omics studies that stop at association, this work directly demonstrates causality through precise functional experiments: -CBS K386R mutation: Substituting lysine with arginine increased hydrogen sulfide (H₂S) production, enhancing a known pro-longevity metabolic pathway linked to caloric restriction and stress resilience. -USP10 K714 acetylation: Acetylating this site decreased PCNA stability, contributing to enhanced cancer resistance — a major evolutionary pressure in large, long-lived mammals. These results show that specific acetylation changes actively drive pro-longevity mechanisms, not just associate with them. 🧩 Implications for longevity science and therapeutics: -Acetylation patterns could serve as a new functional biomarker for biological aging. -Targeting enzymes like SIRT6 or modulating acetylation states could lead to precision therapies that stabilize mitochondrial metabolism and enhance genome maintenance. -The future of aging research may increasingly focus not only on DNA sequences, but on the dynamic regulation of protein function through PTMs. This study highlights a profound shift: longevity is encoded not just in genes, but in how proteins are chemically modified across evolution. 📚 Full paper: https://lnkd.in/edgvumga 🔬 PHARAOH tool (GitHub): https://lnkd.in/e9Fci9CH 📊 Mass spec dataset: https://lnkd.in/ex9x9URf #proteomics #agingresearch #longevityscience #bioinformatics #acetylation #healthspan #lifespanextension #mitochondria #longevity

NotebookLM: This publication addresses DNA damage as a primary driver of aging and age-related diseases, including cancer and neurodegeneration. It explores therapeutic strategies aimed at mitigating these effects, focusing on enhancing DNA repair mechanisms and targeting the DNA damage response (DDR). The authors discuss approaches such as eliminating senescent cells (senolytics), modulating inflammatory responses triggered by DNA damage, and boosting intrinsic DNA repair capacities through methods like NAD+ supplementation and gene therapy. The paper also introduces the DREAM complex as a potential "master regulator" for broadly increasing somatic cell DNA repair, akin to the robust repair seen in germline cells, which could pave the way for new anti-aging interventions. https://lnkd.in/eGm97V7Q "The recognition of the widespread consequences of DNA damage to the functional integrity of cells has provided a more complete picture of the underlying mechanisms of ageing and risk factors for age-related diseases3. DNA repair is one of the most conserved complex molecular processes in a cell. The plethora of distinct lesion types and the irreplaceability of the nuclear genome underscore the unique role of genome maintenance among longevity assurance systems. As human life expectancy continues to increase, the need for effective interventions to maintain genome integrity becomes ever more critical for sustaining health and longevity in ageing populations and mitigating the age-dependent cancer risk. Today, strategies that target some of the phenotypic consequences of DNA damage, collectively called the DNA damage response or DDR, including cancer, inflammation and cellular senescence, are in clinical trials or close to clinical translation." "It is thus pertinent to implement ageing biomarkers, such as biological ageing clocks, as clinical study endpoints. Clearly, the ageing clocks need clinical validation and must be able to detect individual ageing trajectories and personal disease risks. Such ageing biomarkers could then be applied to ascertain geroprotective effectiveness and control side effects of such long-term treatments. The emerging concept of treating ageing at its root cause, by improving overall DNA repair, could enable a healthy ageing society of the future." https://lnkd.in/eqqGDgTQ

"From geroscience to precision geromedicine: Understanding and managing aging" A great resource just published in Cell by Cell Press by a stellar group of authors, Guido KROEMER, Andrea B. Maier, Ana Maria Cuervo (Albert Einstein College of Medicine), Vadim Gladyshev, Luigi Ferrucci, Vera Gorbunova, Brian Kennedy, Thomas Rando, Andrei Seluanov, Felipe Sierra, Eric Verdin and Carlos López-Otin (Universidad Nebrija). This review article provides an outline of a roadmap from the current state of "geroscience" (defined as the field of inquiry dedicated to the identification of ACTIONABLE hallmarks of aging) to actual interventions, which the authors argue require precision medicine -"pending results from randomized clinical trials and regulatory approval, gerotherapeutics will be tailored to each person based on their genetic profile, high-dimensional omics-based biomarkers of aging, clinical and digital biomarkers of aging, psychosocial profile, and past or present exposures." They contrast 3 different descriptive frameworks: 1️⃣ The 13/14 hallmarks of aging, biological phenomena that associate "causally" with aging (e.g., telomere attrition, epigenetic alterations, cellular senescence, stem cell exhaustion, chronic inflammation, dysbiosis) 2️⃣ Diseases of aging are probably the most familiar to the general public, e.g., cancer, cardiovascular disease, sarcopenia (muscle loss), neurodegeneration. Such diseases are related to the hallmarks in complex ways: they are in a way the emergent outcome of many interacting processes. 3️⃣ Gerogenes and gerosuppressors, involved in pathways that impact directly one or more diseases of aging. The idea is that "biological aging can be viewed as a process that is not only modulated by the environment but also accelerated by the activation of gerogenes and the inactivation of gerosuppressive genes". The identification of these genes (and their presence or absence in a patient) can lead to personalized therapeutic routes. The picture here shows multiple genes and their involvement in a number of diseases of aging. Some have a narrow impact on one disease, but many affect more than one disease, suggesting that targeting these genes or their products may have an overall aging effect. I will leave with this quote: "Theoretically, to obtain broad drug effects on multiple age-related diseases, at least one of two conditions should be fulfilled. Either the drug should target the root causes of several diseases, ideally the entire aging process, or, alternatively, the disease-specific process that is targeted (e.g., hyperglycemia or dyslipidemia) should be involved in disease-aggravating feedforward loops that involve several organ systems (e.g., the metabolic, cardiovascular, and immune/inflammatory systems), thus compromising general health"

Researchers at Weill Cornell Medicine and the epigenetics company TruDiagnostic have uncovered DNA markers associated with retroelements, remnants of ancient viral genetic material, in our genes that act as highly accurate epigenetic clocks predicting chronological age. The results support the idea that certain retroelements in the human genome may be involved in aging. New Epigenetic Clock: “Retro-Age” predicts biological age using DNA markers from ancient viral elements. Impact on Aging: Retroelement activity linked to inflammation and genomic instability in aging. Therapeutic Potential: Findings could guide anti-aging treatments and monitor their effectiveness. Retroelements have been known to impact gene regulation, gene expression, genomic stability and the trajectory of various human diseases, but their potential as biomarkers for aging had been largely unexplored. The study, published in Aging Cell, concluded that these retroelement clocks embedded in the human genome capture unique signals of aging not previously recognized by other clocks that measure chronological age. Most aging clocks estimate a person's biological age based on patterns of epigenetic markers—chemical tags called methyl groups that are attached to DNA and affect how genes are expressed. The pattern of methylation on retroelements seems to change as people age, causing some genes to be more active, which may lead to genomic instability, inflammation and age-related diseases. Aging is a complex process influenced by genetic, environmental and epigenetic factors, with researchers pursuing reliable markers that can predict biological age—a snapshot of a person's age at the biochemical level that impacts health and overall well-being. On the other hand, chronological age represents the number of years a person has lived. Depending on the individual, the two may not correlate. https://lnkd.in/gidYzSNi

Scientists discovered a critical gene for longevity! In a groundbreaking discovery, researchers at the University of Copenhagen (Københavns Universitet) have identified a protein, OSER1, which may play a critical role in regulating lifespan across multiple species, including humans. The study, published in Nature Communications, explores how OSER1—regulated by the well-known transcription factor FOXO—affects oxidative stress response and longevity. Key Aspects of the Discovery: OSER1 is an evolutionarily conserved protein found in a variety of species, including fruit flies, nematodes, silkworms, and humans. This evolutionary conservation indicates its fundamental role in biological processes linked to aging. The overexpression of OSER1 in flies and other model organisms has been shown to enhance resistance to oxidative stress, starvation, and heat shock. In contrast, the depletion of OSER1 leads to increased reactive oxygen species (ROS), mitochondrial dysfunction, and reduced ATP production—key factors contributing to cellular aging. OSER1 is a target gene regulated by FOXO transcription factors, which are central players in the longevity regulatory network. FOXO’s involvement makes OSER1 a highly relevant factor in aging-related pathways, providing insight into how cells manage stress and maintain mitochondrial integrity. Proteomic analysis in humans suggests OSER1’s role in oxidative stress response, cellular senescence, and reproduction. This connection could make OSER1 a potential target for developing therapeutic interventions aimed at slowing the aging process and preventing age-related diseases such as cardiovascular and neurodegenerative conditions. Incidentally, I’ve just came back from the University of Copenhagen where the 11th Aging Research and Drug Discovery Meeting (#ARDD2024) took place, and I am still under the impression that Copenhagen is a place to be if you are in Europe and involved in aging research. Really looking forward to #ARDD2025! #agingresearch #longevity #science #research Image credit: Nature Communications

I thoroughly enjoyed collaborating with my colleagues Amanat Ali and Sofiya Milman on this study, where the role of rare functional coding variants in the IGF-1 gene is explored in individuals with exceptional longevity. The insulin/IGF-1 signaling pathway has long been associated with lifespan regulation in model organisms, but its impact in human longevity remained unclear. This study, using whole exome sequencing data from Ashkenazi Jewish centenarians and all-atom molecular dynamics simulations to characterize two identified key variants: - IGF-1:p.Ile91Leu – A novel, centenarian-specific variant that weakens IGF-1 binding to its receptor, potentially reducing IGF-1 signaling. - IGF-1:p.Ala118Thr – A variant significantly associated with lower circulating IGF-1 levels. These findings add to the growing evidence that modulating IGF-1 signaling could be a key factor in extending human lifespan. Could this open new avenues for aging research and therapeutics? Full study here: https://lnkd.in/e_VWvfuP #Longevity #IGF1 #AgingResearch #Genetics #Lifespan #MolecularBiology