本期节目深入探讨了衰老研究的前沿动态，生物学家Brian Kennedy分享了人体衰老研究的最新见解，包括雷帕霉素的临床试验以及剂量、时机和运动如何影响结果。节目还介绍了两种衰老模型，并解释了传统模型为何不足。Kennedy团队正致力于开发更具临床实用性的生物钟。此外，节目还讨论了α-酮酸、尿石素A和NAD增强剂的潜力，以及VO2 max训练、力量训练和GLP-1、SGLT2药物等生活方式干预如何促进更长久、更健康的生活。

🔬 **衰老模型与生物钟更新**：传统衰老模型被认为不足以解释生物衰退的复杂性。Kennedy提出，衰老并非简单的线性累积，而是涉及指数级死亡风险的上升。他强调，目前大多数衰老生物标志物缺乏临床实用性，并介绍了其团队正致力于开发更具行动力的生物钟，以期实现更主动的健康管理。

⚡ **mTOR信号与雷帕霉素的潜力**：炎症和mTOR信号通路被认为是衰老的核心驱动因素。雷帕霉素作为一种潜在的衰老干预药物，可能通过调控mTOR信号通路，延缓衰老过程并增强免疫力。Kennedy团队正在进行雷帕霉素在人体内的临床试验，以探索其在剂量、时机和与运动结合方面的最佳应用策略。

💪 **力量、体能与健康寿命**：研究表明，肌肉、力量和整体体能是预测健康寿命的最强指标。节目强调了VO2 max训练、力量训练等生活方式干预对提升健康水平的重要性，并探讨了GLP-1和SGLT2类药物在促进长寿方面的作用。

🧬 **基因与长寿干预的平衡**：节目探讨了表观遗传学在衰老中的作用，并指出了甲基化时钟的局限性。在追求长寿的同时，也需要平衡对延长寿命和改善晚年健康寿命的迫切需求。此外，文章还提醒，过度叠加多种长寿干预措施可能适得其反，需要谨慎对待。

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Brian Kennedy is a renowned biologist, leader in aging research, and director of the Center for Healthy Longevity at the National University of Singapore. In this episode, Brian shares insights from ongoing human aging studies, including clinical trials of rapamycin and how dosing strategies, timing, and exercise may influence outcomes. He presents two key models of aging—one as a linear accumulation of biological decline and the other as an exponential rise in mortality risk—and explains why traditional models of aging fall short. He also explains why most current aging biomarkers lack clinical utility and describes how his team is working to develop a more actionable biological clock. Additional topics include the potential of compounds like alpha-ketoglutarate, urolithin A, and NAD boosters, along with how lifestyle interventions—such as VO2 max training, strength building, and the use of GLP-1 and SGLT2 drugs—may contribute to longer, healthier lives.

We discuss:

Brian’s journey from the Buck Institute to Singapore, and the global evolution of aging research [2:45]; Rethinking the biology of aging: why models like the hallmarks of aging fall short [9:45]; How inflammation and mTOR signaling may play a central, causal role in aging [14:15]; The biological role of mTOR in aging, and the potential of rapamycin to slow aging and enhance immune resilience [17:30]; Aging as a linear decline in resilience overlaid with non-linear health fluctuations [22:30]; Speculating on the future of longevity: slowing biological aging through noise reduction and reprogramming [33:30]; Evaluating the role of the epigenome in aging, and the limits of methylation clocks [39:00]; Balancing the quest for immortality with the urgent need to improve late-life healthspan [43:00]; Comparing the big 4 chronic diseases: which are the most inevitable and modifiable? [47:15]; Exploring potential benefits of rapamycin: how Brian is testing this and other interventions in humans [51:45]; Testing alpha-ketoglutarate (AKG) for healthspan benefits in aging [1:01:45]; Exploring urolithin A’s potential to enhance mitochondrial health, reduce frailty, and slow aging [1:05:30]; The potential of sublingual NAD for longevity, and the combination of NAD and AKG for metabolic and exercise enhancement [1:09:00]; Other interventions that may promote longevity: spermidine, 17𝛼-estradiol, HRT, and more [1:17:00]; Biological aging clocks, clinical biomarkers, and a new path to proactive longevity care [1:23:15]; Evaluating rapamycin, metformin, and GLP-1s for longevity in healthy individuals [1:32:15]; Why muscle, strength, and fitness are the strongest predictors of healthspan [1:37:30]; Why combining too many longevity interventions may backfire [1:39:30]; How increased funding and AI integration could accelerate breakthroughs in aging research [1:41:45]; The research Brian is most excited about, and the need to balance innovation with safety in longevity clinics [1:47:00]; Peter’s reflections on emerging interventions and the promise of combining proven aging compounds [1:54:00]; and More.

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