<p class="ql-block"><b style="font-size:15px;"><i>現(xiàn)代衰老學前沿（37）</i></b></p> <p class="ql-block">- 標題：<b style="font-size:20px;">從老年科學到精準老年醫(yī)學：衰老的認知與干預</b></p><p class="ql-block">- 期刊：<b>《細胞》</b></p><p class="ql-block">- 發(fā)表時間：<b>2025年4月17日</b></p><p class="ql-block">- DOI：10.1016/j.cell.2025.03.011</p><p class="ql-block">- 作者：吉多·克羅默、安德里亞·B·邁爾、安娜·瑪麗亞·庫韋羅、瓦季姆·N·格拉德舍夫、路易吉·費魯奇、維拉·戈爾布諾娃、布萊恩·K·肯尼迪、托馬斯·A·蘭多、安德烈·瑟盧阿諾夫、費利佩·塞拉、埃里克·韋爾丹、卡洛斯·洛佩斯-奧廷</p><p class="ql-block">摘要</p><p class="ql-block">在闡明<b>衰老背后的分子、細胞及超細胞機制方面，學界已取得重大進展。這催生了老年科學的誕生</b>，其核心目標是鑒定出可進行干預的衰老標志。衰老可被視作一個由促衰老基因過度激活所推動的過程（促衰老基因即促進生理性衰老的基因與分子通路），而<b>抑衰老因子則可延緩這一進程，這與癌癥由原癌基因激活引發(fā)、抑癌基因發(fā)揮預防作用的模式十分相似</b>。人群研究表明，這類促<b>衰老基因與抑衰老因子通常與增齡相關疾病密切相關</b>，同時也為動物模型中構(gòu)建增齡相關疾病模型、為人類治療與預防此類疾病提供了靶點。促衰老基因與抑衰老因子同環(huán)境、行為及心理風險因素相互作用，共同決定了個體生理性衰老與疾病表型的異質(zhì)性軌跡。新型分子譜分析技術能夠?qū)Υ偎ダ吓c抑衰老通路進行表征，并將其作為衰老生物標志物，由此開啟了精準老年醫(yī)學時代。預計在隨機臨床試驗結(jié)果出爐并獲得監(jiān)管批準后，<b>老年治療藥物將實現(xiàn)個體化定制：依據(jù)個體基因譜、基于多維組學的衰老生物標志物、臨床與數(shù)字化衰老標志物、社會心理特征以及既往與當前暴露因素，為每個人量身制定干預方案。</b></p><p class="ql-block">關鍵詞：衰老；衰老時鐘；抗衰老藥物；動脈粥樣硬化；腫瘤；心血管疾病；糖尿??；表觀遺傳時鐘；基因組學；神經(jīng)退行性疾病；原癌基因；抑癌基因；精準老年醫(yī)學</p><p class="ql-block">引言</p><p class="ql-block"><b>衰老是絕大多數(shù)慢性疾病的主要危險因素，包括心血管疾病、糖尿病、神經(jīng)退行性疾病與腫瘤</b>。過去二十年間，人類在解析衰老生物學基礎方面取得了前所未有的突破，成功<b>鑒定出跨物種保守、可調(diào)控衰老的分子與細胞通路</b>。這些成果為老年科學奠定了基礎，該學科致力于將基礎衰老研究轉(zhuǎn)化為可延長健康壽命、預防增齡相關疾病的干預手段。</p><p class="ql-block"><b>衰老標志概念于2013年首次提出，并在2023年得到拓展，為理解復雜的衰老生物學提供了統(tǒng)一框架。這類標志需滿足三項判定標準：</b>（1）在正常衰老過程中持續(xù)顯現(xiàn)；</p><p class="ql-block">（2）實驗性加劇該特征會加速衰老；</p><p class="ql-block">（3）改善該特征可延緩衰老并延長健康壽命。</p><p class="ql-block"><b>本綜述將衰老標志更新至14項</b>，新增兩項標志：細胞外基質(zhì)改變與社會心理隔離。我們進一步闡述了分別驅(qū)動與抑制衰老的促衰老基因與抑衰老因子概念，并探討該框架如何應用于精準老年醫(yī)學——這一新興領域可根據(jù)個體生物學特征定制抗衰老干預方案。</p><p class="ql-block">衰老標志：拓展后的框架</p><p class="ql-block"><b>原發(fā)標志（衰老驅(qū)動因素）</b></p><p class="ql-block"><b>1. 基因組不穩(wěn)定性</b>：內(nèi)外源應激導致DNA損傷與突變不斷累積。</p><p class="ql-block"><b>2. 端粒損耗</b>：細胞每分裂一次，染色體末端便逐步縮短，最終引發(fā)細胞衰老。</p><p class="ql-block"><b>3. 表觀遺傳改變</b>：DNA甲基化、組蛋白修飾及染色質(zhì)結(jié)構(gòu)異常，導致基因表達紊亂。</p><p class="ql-block"><b>4. 蛋白穩(wěn)態(tài)喪失</b>：蛋白質(zhì)折疊、降解與清除功能受損，引發(fā)錯誤折疊蛋白聚集。</p><p class="ql-block"><b>5. 巨自噬功能障礙</b>：細胞清除受損細胞器與蛋白質(zhì)的回收系統(tǒng)功能衰退。</p><p class="ql-block">拮抗標志（代償性反應）</p><p class="ql-block"><b>6. 營養(yǎng)感應失調(diào)</b>：胰島素/IGF-1、雷帕霉素靶蛋白（mTOR）、腺苷酸活化蛋白激酶（AMPK）、沉默信息調(diào)節(jié)因子（sirtuins）等營養(yǎng)感知通路調(diào)控失衡。</p><p class="ql-block"><b>7. 線粒體功能障礙</b>：線粒體功能下降、活性氧生成增加、能量代謝受損。</p><p class="ql-block"><b>8. 細胞衰老</b>：不可逆停滯的細胞不斷累積，并分泌促炎癥因子（衰老相關分泌表型SASP）。</p><p class="ql-block">整合標志（系統(tǒng)性表現(xiàn)）</p><p class="ql-block"><b>9. 干細胞耗竭</b>：成體干細胞數(shù)量減少、功能異常，組織修復與再生能力受損。</p><p class="ql-block"><b>10. 細胞間通訊改變</b>：細胞間激素、免疫及神經(jīng)信號傳導被破壞。</p><p class="ql-block"><b>11. 慢性炎癥（炎性衰老）</b>：由衰老相關分泌表型、微生物菌群失調(diào)及細胞損傷引發(fā)的低度持續(xù)性炎癥。</p><p class="ql-block"><b>12. 菌群失調(diào)：</b>腸道微生物組成與功能失衡，影響代謝與免疫功能。</p><p class="ql-block"><b>13. 細胞外基質(zhì)（ECM）改變</b>：基質(zhì)硬化、交聯(lián)與降解，破壞組織結(jié)構(gòu)與功能。</p><p class="ql-block"><b>14. 社會心理隔離</b>：社交脫節(jié)與孤獨感，通過神經(jīng)內(nèi)分泌應激通路加速衰老。</p><p class="ql-block"><b>促衰老基因與抑衰老因子</b>：衰老的分子基礎與腫瘤領域中原癌基因與抑癌基因的模式類似，衰老由促衰老基因（促衰老因子）驅(qū)動，受抑衰老因子（抗衰老因子）拮抗。</p><p class="ql-block">-<b> 促衰老基因</b>：過度激活會加速衰老的基因（如載脂蛋白E ε4、mTOR、核因子κB）。</p><p class="ql-block">- <b>抑衰老因子</b>：激活或上調(diào)可延緩衰老的基因（如克洛索基因、叉頭框O3、沉默信息調(diào)節(jié)因子1、端粒酶逆轉(zhuǎn)錄酶）。</p><p class="ql-block">這些基因與環(huán)境因素（飲食、運動、毒素）、社會心理因素（壓力、隔離）共同塑造了個體的衰老軌跡。</p><p class="ql-block">精準老年醫(yī)學：從老年科學走向臨床應用精準老年醫(yī)學整合多組學數(shù)據(jù)、臨床生物標志物與社會心理因素，實現(xiàn)三大目標：</p><p class="ql-block">1. <b>衰老診斷</b>：量化生物學年齡，識別高風險衰老表型。</p><p class="ql-block">2. <b>衰老防護</b>：針對特定衰老標志，定制生活方式、藥物、細胞治療等干預手段。</p><p class="ql-block">3. 衰老治療：靶向衰老核心機制，治療增齡相關疾病。</p><p class="ql-block">核心工具包括表觀遺傳時鐘、蛋白質(zhì)組/代謝組檢測平臺、數(shù)字化生物標志物（可穿戴設備、認知測試）。</p><p class="ql-block"><b>挑戰(zhàn)與未來方向</b></p><p class="ql-block">- 驗證：需開展大規(guī)模臨床試驗證實老年治療藥物的有效性。</p><p class="ql-block">- 異質(zhì)性：衰老在個體間、器官間存在顯著差異。</p><p class="ql-block">- 倫理：抗衰老干預的可及性、公平性與監(jiān)管規(guī)范。</p><p class="ql-block">- 整合：融合生物學、社會與環(huán)境因素，實現(xiàn)全人關懷。</p><p class="ql-block">結(jié)論</p><p class="ql-block"><b>將衰老標志拓展至14項（包含細胞外基質(zhì)改變與社會心理隔離），體現(xiàn)了衰老兼具生物學與社會學屬性的整體認知。促衰老基因/抑衰老因子框架為精準老年醫(yī)學提供了發(fā)展路線圖，有望通過個體化干預延長健康壽命，減輕增齡相關疾病帶來的社會負擔。</b></p><p class="ql-block"><br></p><p class="ql-block">核心參考文獻</p><p class="ql-block">1. López-Otín, C., 等. (2013). 衰老的標志. 《細胞》, 153(6), 1194–1217.</p><p class="ql-block">2. López-Otín, C., 等. (2023). 衰老標志：不斷拓展的研究體系. 《細胞》, 186(2), 243–278.</p><p class="ql-block">3. Kroemer, G., 等. (2025). 從老年科學到精準老年醫(yī)學. 《細胞》, 186(8), 2043–2062.</p> <p class="ql-block">論文基本信息</p><p class="ql-block"> - 標題：<b>From geroscience to precision geromedicine: Understanding and managing aging </b></p><p class="ql-block">- 期刊：<b>Cell</b></p><p class="ql-block">- 發(fā)表時間：<b>2025-04-17</b></p><p class="ql-block">- DOI：10.1016/j.cell.2025.03.011 </p><p class="ql-block">-<b> 作者：Guido Kroemer, Andrea B Maier, Ana Maria Cuervo, Vadim N Gladyshev, Luigi Ferrucci, Vera Gorbunova, Brian K Kennedy, Thomas A Rando, Andrei Seluanov, Felipe Sierra, Eric Verdin, Carlos López-Otín </b></p><p class="ql-block"> </p><p class="ql-block">全文（英文原版）</p><p class="ql-block"><b>Abstract</b></p><p class="ql-block">Major progress has been made in elucidating the molecular, cellular, and supracellular mechanisms underlying aging. This has spurred the birth of geroscience, which aims to identify actionable hallmarks of aging. Aging can be viewed as a process that is promoted by overactivation of gerogenes, i.e., genes and molecular pathways that favor biological aging, and alternatively slowed down by gerosuppressors, much as cancers are caused by the activation of oncogenes and prevented by tumor suppressors . Such gerogenes and gerosuppressors are often associated with age-related diseases in human population studies but also offer targets for modeling age-related diseases in animal models and treating or preventing such diseases in humans . Gerogenes and gerosuppressors interact with environmental, behavioral, and psychological risk factors to determine the heterogeneous trajectory of biological aging and disease manifestation . New molecular profiling technologies enable the characterization of gerogenic and gerosuppressive pathways, which serve as biomarkers of aging, hence inaugurating the era of precision geromedicine . It is anticipated that, 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 .</p><p class="ql-block"><b>Keywords</b>: aging; aging clocks; anti-aging drugs; atherosclerosis; cancer; cardiovascular diseases; diabetes; epigenetic clocks; genomics; neurodegeneration; oncogene; oncosuppressors; precision geromedicine </p><p class="ql-block"><b>Introduction</b></p><p class="ql-block">Aging is the major risk factor for most chronic diseases, including cardiovascular diseases, diabetes, neurodegeneration, and cancer. The past two decades have witnessed unprecedented progress in understanding the biological basis of aging, leading to the identification of evolutionarily conserved molecular and cellular pathways that modulate aging across species . This progress has laid the foundation for geroscience, a field that seeks to translate basic aging research into interventions that extend healthspan and prevent age-related diseases.</p><p class="ql-block">The concept of hallmarks of aging, first proposed in 2013 and expanded in 2023, has provided a unifying framework for understanding the complex biology of aging. These hallmarks are defined by three criteria: (1) they manifest during normal aging; (2) their experimental exacerbation accelerates aging; and (3) their amelioration slows aging and extends healthspan. In this review, we update the hallmarks of aging to 14, incorporating two new hallmarks: extracellular matrix changes and psychosocial isolation. We further discuss the concept of gerogenes and gerosuppressors, which drive or inhibit aging, respectively, and explore how this framework can be applied to precision geromedicine—an emerging approach that tailors anti-aging interventions to individual biological profiles .</p><p class="ql-block">The Hallmarks of Aging: An Expanded Framework</p><p class="ql-block"><b>Primary Hallmarks (Drivers of Aging)</b></p><p class="ql-block">1. Genomic instability: Accumulation of DNA damage and mutations due to exogenous and endogenous stressors.</p><p class="ql-block">2. Telomere attrition: Progressive shortening of chromosome ends with each cell division, leading to cellular senescence.</p><p class="ql-block">3. Epigenetic alterations: Changes in DNA methylation, histone modifications, and chromatin structure that disrupt gene .</p><p class="ql-block">4. Loss of proteostasis: Impaired protein folding, degradation, and clearance, leading to aggregation of misfolded proteins.</p><p class="ql-block">5. Disabled macroautophagy: Diminished cellular recycling system that removes damaged organelles and proteins.</p><p class="ql-block"><b>Antagonistic Hallmarks (Compensatory Responses)</b></p><p class="ql-block">6. Deregulated nutrient sensing: Dysregulation of pathways like IGF-1/insulin, mTOR, AMPK, and sirtuins that sense nutrients.</p><p class="ql-block">7. Mitochondrial dysfunction: Decline in mitochondrial function, increased reactive oxygen species production, and impaired energy metabolism.</p><p class="ql-block">8. Cellular senescence: Accumulation of irreversibly arrested cells that secrete pro-inflammatory factors (SASP).</p><p class="ql-block">Integrative Hallmarks (Systemic Manifestations)</p><p class="ql-block"> </p> <p class="ql-block">9. Stem cell exhaustion: Depletion and dysfunction of adult stem cells, impairing tissue repair and regeneration.</p><p class="ql-block">10. Altered intercellular communication: Disruption of hormonal, immune, and neural signaling between cells.</p><p class="ql-block">11. Chronic inflammation (inflammaging): Low-grade, persistent inflammation driven by SASP, microbial dysbiosis, and cellular damage.</p><p class="ql-block">12. Dysbiosis: Imbalance in gut microbiota composition and function, affecting metabolism and immunity.</p><p class="ql-block">13. Extracellular matrix (ECM) changes: Stiffening, cross-linking, and degradation of ECM, impairing tissue structure and function.</p><p class="ql-block">14. Psychosocial isolation: Social disconnection and loneliness, accelerating aging via neuroendocrine stress pathways.</p><p class="ql-block"><b>Gerogenes and Gerosuppressors: The Molecular Basis of Aging</b></p><p class="ql-block">Analogous to oncogenes and tumor suppressors in cancer, aging is driven by gerogenes (pro-aging factors) and opposed by gerosuppressors (anti-aging factors) .</p><p class="ql-block">- Gerogenes: Genes whose overactivation accelerates aging (e.g., APOE ε4, mTOR, NF-κB).</p><p class="ql-block">- Gerosuppressors: Genes whose activation or upregulation slows aging (e.g., Klotho, FOXO3, SIRT1, TERT).</p><p class="ql-block">These genes interact with environmental factors (diet, exercise, toxins) and psychosocial factors (stress, isolation) to shape individual aging trajectories .</p><p class="ql-block">Precision Geromedicine: Translating Geroscience to Clinical Practice</p><p class="ql-block">Precision geromedicine integrates multi-omics data, clinical biomarkers, and psychosocial factors to:</p><p class="ql-block">1. Gero-diagnostics: Quantify biological age and identify high-risk aging phenotypes.</p><p class="ql-block">2. Gero-protection: Tailor interventions (lifestyle, pharmacology, cell therapy) to target specific hallmarks.</p><p class="ql-block">3. Gero-therapy: Treat age-related diseases by targeting underlying aging mechanisms.</p><p class="ql-block">Key tools include epigenetic clocks, proteomic/metabolomic panels, and digital biomarkers (wearables, cognitive tests) .</p><p class="ql-block">Challenges and Future Directions</p><p class="ql-block">- Validation: Need large clinical trials to confirm gerotherapeutics efficacy .</p><p class="ql-block">- Heterogeneity: Aging varies widely between individuals and organs .</p><p class="ql-block">- Ethics: Access, equity, and regulation of anti-aging interventions .</p><p class="ql-block">- Integration: Combine biological, social, and environmental factors for holistic care .</p><p class="ql-block"><b>Conclusion</b></p><p class="ql-block">The expansion of aging hallmarks to 14, including ECM changes and psychosocial isolation, reflects a holistic view of aging as a biological and social process. The gerogene/gerosuppressor framework provides a roadmap for precision geromedicine, promising personalized interventions to extend healthspan and reduce age-related disease burden .</p><p class="ql-block">參考文獻（核心）</p><p class="ql-block">1. López-Otín, C., et al. (2013). The hallmarks of aging. Cell, 153(6), 1194–1217.</p><p class="ql-block">2. López-Otín, C., et al. (2023). Hallmarks of aging: An expanding universe. Cell, 186(2), 243–278.</p><p class="ql-block">3. Kroemer, G., et al. (2025). From geroscience to precision geromedicine. Cell, 186(8), 2043–2062.</p>