Ep. 1: Targeting Biological Aging: A New Paradigm for 21st Century Medicine

April 21, 2021

In the kickoff episode of our 2021 series on Aging, Dr. Matt Kaeberlein, Professor of Laboratory Medicine and Pathology at the University of Washington School of Medicine, presents translational geroscience as the emerging paradigm for 21st century medicine, arguing that biological aging rather than individual diseases represents the greatest risk factor for mortality and disability. Unlike traditional disease-first approaches that treat conditions sequentially after onset, Kaeberlein's research identifies interventions targeting the molecular hallmarks of aging itself, which hold potential to prevent multiple age-related diseases simultaneously. Drawing on recent advances in understanding the mechanisms linking biological aging to disease, he discusses his work with rapamycin and other interventions designed to enhance healthspan and lifespan across diverse populations.

Key Highlights

• Biological aging is the greatest risk factor for nearly every major cause of death and disability, including COVID-19, making it a more effective therapeutic target than treating individual diseases one at a time.
• Interventions that directly target the molecular hallmarks of aging have the potential to prevent multiple diseases of aging simultaneously, rather than achieving incremental gains through disease-specific approaches.
• Recent advances in geroscience have identified translational interventions like rapamycin that can enhance both healthspan and lifespan in companion dogs and people, opening new avenues for preventive medicine.

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Ep. 2: The Challenges of Sarcopenia: Definition, Underlying Mechanisms, Interventions, and Outcomes

May 19, 2021

Dr. Charlotte A. Peterson, Joseph Hamburg Endowed Professor and Director of the Center for Muscle Biology at the University of Kentucky, and Dr. Jack Guralnik, Professor of Epidemiology and Public Health at the University of Maryland School of Medicine, address sarcopenia, the age-related loss of muscle mass and strength beginning around age 30 that leads to functional decline and frailty. The webinar examines how inconsistent diagnostic definitions create large variations in disease prevalence and discusses emerging diagnostic approaches using deuterium-labelled creatine dilution, while exploring current therapeutic interventions including metformin and senolytic drugs despite the absence of FDA-approved treatments. Peterson and Guralnik emphasize the need for standardized clinical outcome assessments and regulatory frameworks to advance treatment development for aging populations.

Key Highlights

• Sarcopenia affects muscle mass, strength, and functional capacity beginning around age 30, and while universal aging causes some muscle loss, accelerated rates occur from sedentary lifestyle, hospitalization, and extended bed rest, with no drugs currently approved for treatment.
• Inconsistent definitions of sarcopenia using grip strength, gait speed, and lean mass across Europe and the US lead to large differences in prevalence rates and diagnostic discordance, necessitating standardized assessment methods and regulatory frameworks.
• Emerging interventions including metformin and senolytic drugs show promise in preventing age-associated muscle loss and enhancing muscle repair following injury in older individuals, though metformin may paradoxically blunt the benefits of exercise on muscle.

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Ep. 3: Experimental Muscle Mechanics in Aging and Disease

June 2, 2021

Dr. Rizwan Qaisar, Assistant Professor of Basic Medical Sciences at the College of Medicine, University of Sharjah, and Matt Borkowski, General Manager at Aurora Scientific, present cutting-edge experimental approaches for measuring muscle function across in vivo, in vitro, and in situ settings to understand sarcopenia and age-related muscle impairment. The webinar explores how advanced instrumentation including the Dual Mode Lever System and Single Permeabilized Fiber System enable detailed characterization of muscle mechanics while isolating contractile mechanisms. Qaisar discusses the molecular basis of sarcopenia and reviews emerging interventions including restoration of sarcoplasmic reticulum calcium handling and circulating biomarkers for disease assessment. Sponsored by Aurora Scientific.

Key Highlights

• Advanced muscle physiology systems enable complex experimental protocols beyond maximal isometric strength measurements, allowing researchers to model real-life muscle function in aging and disease conditions using longitudinal assessments as animals age.
• Sarcopenia begins in humans in their late 20s or early 30s with approximately 1-2% annual decreases in muscle strength and 3-4% decreases in muscle power, and can be accelerated by secondary conditions including COPD, heart failure, Parkinson's disease, neurodegenerative diseases, and COVID-19.
• Emerging interventions including restoration of sarcoplasmic reticulum calcium ATPase (SERCA) via CDN1163 show rare ability to restore muscle mass in aging mice, while blood and urine biomarkers such as CAF22 provide predictive assessments of muscle health in disease states.

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Ep. 4: Aging and Bone Health

June 22, 2021

Dr. Joy Wu, Associate Professor of Endocrinology at Stanford University School of Medicine, examines the pathophysiology of age-related bone loss and osteoporosis, focusing on the imbalance between bone formation by osteoblasts and bone resorption by osteoclasts driven by hormonal changes, cellular senescence, inflammation, and sarcopenia. The webinar reviews current clinical approaches including bone resorption inhibitors such as bisphosphonates and estrogen receptor modulators, as well as anabolic therapies including teriparatide and romosuzumab that promote bone formation through PTH1R and Wnt signaling pathways. Wu discusses emerging stem cell-based regenerative therapies using induced pluripotent stem cells and mesenchymal stem cell sources to potentially reverse osteoporotic damage and restore skeletal function.

Key Highlights

• Osteoporosis affects approximately 50% of women and 25% of men over age 50, with bone density peaking in the mid to late 20s followed by progressive decline and accelerated loss in women during menopause, resulting in increasing osteopenia and fracture risk with age.
• PTH1R signaling through G protein pathways and interactions with Wnt signaling are critical regulators of mesenchymal progenitor commitment to osteoblast differentiation, with parathyroid hormone inhibiting sclerostin to promote bone formation, mechanisms targeted by anabolic osteoporosis therapies.
• Stem cell-based approaches using induced pluripotent stem cells differentiated into mature osteoblasts in vitro show promise for skeletal regenerative medicine, offering potential to reverse osteoporosis and treat orthopedic injuries while avoiding teratoma formation risks associated with in vivo pluripotent cell injection.

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Ep. 5: Quality, Quantity and Timing: Regulating Healthspan and Lifespan With Diet

‍July 7, 2021

Dr. Dudley Lamming, Associate Professor in the Division of Endocrinology, Diabetes and Metabolism at the University of Wisconsin-Madison, investigates how dietary composition, quantity, and timing regulate metabolic health and longevity through nutrient-responsive signaling pathways. Using mouse models, his research demonstrates that both caloric restriction and fasting independently contribute to lifespan extension, with fasting alone proving sufficient to improve metabolism and gene expression profiles. The webinar reveals counter-intuitive findings that low-protein and low branched-chain amino acid diets enhance metabolic health markers including glucose tolerance and reduced weight gain, effects mediated partially by the insulin-sensitizing hormone FGF21. Sponsored by Columbus Instruments.

Key Highlights

• Fasting components of calorie-restricted diets are essential for metabolic and transcriptional benefits, with time-restricted eating and imposed fasting alone sufficient to improve metabolic health independent of total caloric restriction.
• Low-protein and low branched-chain amino acid diets, particularly restriction of isoleucine and valine, improve glucose tolerance and reduce weight gain despite increased food intake, challenging historical assumptions about protein as uniformly beneficial.
• Dietary branched-chain amino acids, especially isoleucine proportion of total protein, are potent regulators of glucose tolerance and energy expenditure through FGF21-dependent and independent mechanisms, with early-life low BCAA diet extending lifespan in males.

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Ep. 6: Malignant Brain Aging: The Formidable Link to Neurodegeneration

July 28, 2021

Dr. Suzanne de la Monte, Professor of Pathology and Laboratory Medicine and Neurosurgery at Brown University, examines how malignant brain aging and neurodegeneration result from fundamental defects in insulin and insulin-like growth factor signaling, proposing Alzheimer's disease as a form of "Type 3" diabetes characterized by brain insulin resistance. The webinar explores how aging compromises critical brain cell types including astrocytes, oligodendrocytes, and microglia, disrupting blood-brain barrier integrity and triggering neuroinflammation and neuronal dysfunction. De la Monte demonstrates that early deficits in glucose utilization and impaired insulin signaling pathways correlate with Alzheimer's disease severity, and discusses how lifestyle interventions targeting insulin resistance through diet and exercise may improve cognitive outcomes.

Key Highlights

• Malignant brain aging involves loss of homeostasis through senescence, mitochondrial dysfunction, oxidative stress, neuroinflammation, and microvascular dysfunction affecting neurons, oligodendrocytes, astrocytes, and microglia, with disrupted blood-brain barrier integrity allowing entry of damaging substances into the central nervous system.
• Alzheimer's disease is characterized by early deficits in the brain's ability to utilize glucose and resistance to insulin and IGF-1 signaling, which regulate neuronal survival and function, leading to the concept of AD as "Type 3" diabetes with both insulin deficiency and insulin resistance.
• Mortality rates from Alzheimer's disease have climbed in parallel with diabetes mortality since 1980, and lifestyle interventions including exercise and dietary modifications that reduce insulin resistance offer potential to improve cognition through combined cardiovascular, cerebrovascular, and metabolic effects on brain insulin responsiveness.

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Ep. 7: From "Artificial" to "Real": What 24/7 Home Cage Monitoring Teaches Us In Pre-Clinical Neurodegenerative Disease Models

September 15, 2021

Dr. Stefano Gaburro, Scientific Director at Tecniplast, and Dr. Brun Ulfhake, Senior Professor of Laboratory Medicine at Karolinska Institutet, present the Digital Ventilated Cage (DVC) system for continuous, non-invasive monitoring of rodent locomotor activity and behavior in preclinical neurodegenerative disease models. The webinar demonstrates how DVC technology using electromagnetic sensing enables real-time activity tracking without experimenter contact, reducing animal stress while improving data reproducibility in models including SOD mice with amyotrophic lateral sclerosis and Parkinson's disease. Ulfhake discusses how longitudinal home cage monitoring reveals previously hidden behavioral rhythmicities across circadian, weekly, and circannual timescales, revealing that activity patterns are highly dependent on strain, sex, age, housing density, and environmental context.

Key Highlights

• The Digital Ventilated Cage system monitors animal movement four times per second via non-invasive electrodes in the cage base plate without behavioral interference, enabling longitudinal assessment of baseline data across mouse strains and identification of pathological changes in disease models.
• DVC-based monitoring in SOD mice (ALS model) and Parkinson's disease models demonstrates sensitivity to detecting locomotor impairments and validates results against traditional assessment methods like grid inversion testing.
• Home cage monitoring reveals multi-scale activity rhythmicities including circadian patterns, weekly oscillations, and circannual variations entrained within individual cages, demonstrating that activity is context, strain, sex, and age-dependent and providing insights into normal behavior previously undetectable in conventional experimental designs.

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Ep. 8: Aging and Skeletal Muscle Plasticity

September 29, 2021

Professor Sue Bodine, Professor of Medicine at the University of Iowa Carver College of Medicine and Editor-In-Chief of the Journal of Applied Physiology, investigates the mechanisms underlying sarcopenia and the failure of aging muscles to recover mass and function following disuse. Using hindlimb unloading and reloading models in rats, Bodine demonstrates that old animals exhibit greater functional decline and prolonged recovery compared to young animals despite similar degrees of atrophy, revealing that anabolic resistance and neuromuscular junction instability contribute to impaired muscle plasticity. Her research identifies differential gene expression patterns in aging muscles related to denervation, NMJ dysfunction, and proteostatic imbalance that persist during recovery, providing insights into potential therapeutic targets for preventing age-related muscle decline. Sponsored by Aurora Scientific.

Key Highlights

• Old rats display significantly greater decreases in maximum torque following unloading compared to young rats despite similar degrees of atrophy, with incomplete functional recovery even after 14 days of reloading, requiring 28 days to achieve significant improvements in isometric torque compared to immediate recovery in young animals.
• Anabolic resistance in aging muscles results from altered proteostasis including increased mTORC1 activation, increased protein synthesis, inhibited proteasome activity, and increased endoplasmic reticulum stress, preventing appropriate growth responses to mechanical loading cues.
• Neuromuscular junction instability and denervation are enhanced by aging and disuse, with persistent aberrant gene expression of NMJ markers, denervation-associated genes, and atrophy factors in old rats that fail to normalize during recovery, suggesting NMJ dysfunction plays a critical role in age-related muscle plasticity failure.

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Ep. 9: Cardiac Inflammation and Repair Following Myocardial Infraction

October 13, 2021

Dr. Merry Lindsey, Chair of Cellular and Integrative Physiology and Founding Director of the Center for Heart and Vascular Research at the University of Nebraska Medical Center, examines the cellular and molecular mechanisms of cardiac recovery following myocardial infarction, focusing on the balance between extracellular matrix degradation and scar formation. Her research demonstrates that exogenous interleukin-4 treatment promotes macrophage polarization toward an anti-inflammatory M2 phenotype, accelerating the transition from inflammation resolution to cardiac repair. Through development of cardiac metalloproteinase action (CarMA) postulates, Lindsey's work reveals that matrix metalloproteinases including MMP-9 and MMP-12 play protective roles in post-infarction remodeling and inflammation resolution.

Key Highlights

• Exogenous interleukin-4 applied 24 hours after myocardial infarction promotes macrophage polarization toward an M2 anti-inflammatory phenotype, reducing pro-inflammatory markers including CCL3, IL-12a, and TNFα while enhancing anti-inflammatory markers Arg1 and Ym1, and stimulating macrophage-mediated phagocytosis of neutrophils to accelerate inflammation resolution.
• Matrix metalloproteinases including MMP-9 and MMP-12 play protective roles in post-infarction cardiac remodeling, with MMP-12 inhibition paradoxically worsening left ventricular geometry and function through prolonged inflammation and delayed extracellular matrix degradation, demonstrating that upregulated factors after MI often serve cardioprotective roles.
• Understanding the relationship between cardiac inflammation and fibrosis in post-infarction remodeling is critical for identifying at-risk patients who may benefit from early and aggressive therapeutic intervention to promote optimal inflammation resolution and scar formation.

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Ep. 10: Cardiac Glucose Metabolism: Heart Failure in Diabetes and Aging

November 16, 2021

Dr. E. Dale Abel, Chair of the Department of Internal Medicine and Director of the Fraternal Order of Eagles Diabetes Research Center at the University of Iowa, examines how dysfunctional glucose metabolism in diabetes and aging drives cardiomyopathy and heart failure. Abel demonstrates that glucotoxicity impairs mitochondrial function in cardiac muscle through glucose-dependent protein modifications of electron transport chain complexes, with excessive glucose uptake priming the heart for lipotoxic injury and ventricular remodeling. Using metabolomic profiling and left ventricular assistive device outcomes data, his research reveals that mismatches between glucose oxidation and TCA cycle metabolite flux predict poor prognosis, while adaptive glucose metabolic remodeling correlates with cardioprotection and recovery.

Key Highlights

• Macrovascular complications including heart attack and stroke, rather than microvascular complications, drive suffering and mortality in diabetic patients, with nearly half of heart failure hospitalizations occurring in patients with diabetes and intrinsic cardiac muscle defects increasing susceptibility to dysfunction.
• Glucotoxicity causes glucose-dependent protein modifications on mitochondrial electron transport chain complexes in cardiac muscle, impairing mitochondrial function and altering fatty acid metabolism to promote metabolic dysfunction and heart failure, with excessive cardiac glucose uptake priming the heart for lipotoxic injury.
• Metabolomic profiling reveals that mismatches between glucose oxidation rates and TCA cycle metabolite flux directly correlate with poor left ventricular assistive device outcomes, while greater glucose metabolic pathway remodeling predicts improved patient outcomes and cardioprotection, suggesting metabolic targeting as a therapeutic strategy.

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