Age is the largest risk factor for chronic disease, but medicine has yet to develop effective defenses against the most destructive elements of aging. In neurodegenerative disease, age-related protein aggregates have long been implicated in driving cognitive decline. Yet recent treatments approved by the U.S. Food and Drug Administration (FDA) for clearing proteins from the brain demonstrate only minimal impact on delaying the course of disease.

This stark reality strengthens support for new approaches to diseases of aging that address consistent, coordinated degenerative processes directly. Concentrating on the pathways implicated in systemwide decline could lead to remarkable insights, says Mitzi Gonzales, PhD, director of Translational Research at the Jona Goldrich Center for Alzheimer’s and Memory Disorders at Cedars-Sinai.

"We have an opportunity to think beyond core features of disease and focus on understanding the broader pathophysiological mechanisms of decline across multiple organ systems," she said. "The goal is to understand potential intervention pathways to foster both physical and cognitive health, allowing individuals to maintain independence and quality of life in older age."

The drive to discover and disentangle the many complex molecular underpinnings of aging is gaining momentum, bolstering the theory that greater understanding of these processes can point to targets for intervention. An expanding body of preclinical research suggests that mechanisms of aging—inflammation, shifts in immunity and epigenetics, stem cell and metabolic dysfunction, proteostasis, and cellular senescence, among others—are strongly interrelated and can be modulated to halt or prevent the diseases of aging.

"By targeting one or several interconnected mechanisms, we can potentially modify the entire biology of aging," said Nicolas Musi, MD, the Kathi and Gary Cypres Chair in Diabetes Research; vice chair of Translational Research in the Department of Medicine; and director of the Diabetes and Aging Center and the Division of Endocrinology, Diabetes and Metabolism at Cedars-Sinai. "Perhaps aspects of the aging process exist for a reason. There is so much we don’t know in human aging, so almost any direction we go is uncharted waters."

Cedars-Sinai is leading some of the first clinical trials to examine the impacts of drugs and lifestyle interventions on the aging process at the molecular and functional levels. At the newly established Center for Translational Geroscience, experts in metabolic health, brain aging and geriatrics are collaborating with physician-scientists across the organization on diverse questions.

Geriatrician Sara Espinoza, MD, directs the center with co-directors Musi and Gonzales. Espinoza leads a trial into frailty prevention in older adults, while Musi is conducting National Institutes of Health (NIH)-funded clinical trials into the impact of exercise on aging, as well as the intersection of aging, obesity and cellular senescence. Gonzales’ work aims to identify biomarkers of age-related cognitive decline and dementia.

Through longitudinal studies of patients at every stage of age-related disease, the center’s leaders hope to refine biomarkers for early detection. In healthy cohorts, they look to uncover hallmarks of resilience. They seek to better understand heterogeneity in disease development, the widely variable responses to treatment, and whether interventions can impact not just one measure—cognition, for example—but others that generally decline with age, such as muscle strength and cardiac functioning.

"Most geriatric syndromes and conditions are multifactorial," Espinoza said. "Each trial requires careful data collection and collaboration to understand the impact of interventions on aging."

Read: A Daily Dose of Exercise as You Age

Dr. Rosen, Dr. Musi, Dr. Espinoza and Dr. Gonzales are leading geroscience efforts at Cedars-Sinai.

Ticking Clock

The U.S. is rapidly aging; the population of older adults is expected to double to almost 95 million in the next 25 years. The majority of people over 65 live with at least two chronic diseases, take as many as 10-15 medications, and can face a complex and convoluted mindfield of overlapping conditions, disabilities and hospitalizations.

Advanced age is closely associated with a range of diseases, especially dementia and Alzheimer’s disease—a debilitating diagnosis expected to more than double from affecting 5.8 million people in 2020 to affecting 14 million people by 2060. Rates will likely jump for other diseases of aging, as well, including arthritis, cancer, diabetes, depression, life-threatening frailty, obesity, osteoporosis, and kidney and cardiovascular diseases. All this brings into sharp focus concerns about whether medicine is equipped to help patients maintain their health into their 70s and beyond.

But scientists also see rising longevity as an opportunity to gain insight into the wide spectrum of physical and cognitive trajectories. Cedars-Sinai is leading an age-friendly revolution—steered by Chief of Geriatrics Sonja Rosen, MD—to streamline screening and treatment, which could help rein in complications during the sickest, most costly period in a person’s life.

"We have to care about people as they age," Gonzales said.

The $76 billion market for consumer anti-aging products shows no signs of slowing. But specialists stress that only extreme rigor in legitimate clinical trials can ensure accurate and reproducible knowledge.

Geroscience posits that although individuals' aging trajectories vary, inherent and interlinked biological mechanisms are universally responsible for bodily degradation. Preclinical models demonstrate that medications, lifestyle changes and dietary modifications, such as calorie restriction, can slow aging and reduce related conditions. First-of-their-kind clinical trials at Cedars-Sinai examine such "pillars of aging" to further define their role in hopes of leveraging them to prevent disease and promote longevity.

"The body of knowledge about the mechanisms that control aging has grown exponentially over the past 25 years," Musi said. "The time is right to move to clinical trials."

"By targeting one or several interconnected mechanisms, we can potentially modify the entire biology of aging. Perhaps aspects of the aging process exist for a reason. There is so much we don't know in human aging, so almost any direction we go is uncharted waters."

— Nicolas Musi, MD

As part of the NIH-funded Cellular Senescence Network, a trial led by Musi seeks to demonstrate for the first time in humans whether drug interventions effectively clear senescent cells to impact metabolic outcomes, physical function, and overall inflammatory status without interfering in the healthy aging process.

The study will compare three groups: younger patients, older patients who are healthy and older patients with obesity. Participants have been randomized to an exercise and nutrition intervention, the senolytic drug combinationdasatinib plus quercetin (D+Q), or a control group. The study’s investigators hope that analysis of participants’ adipose tissue will unveil how the accumulation of senescent cells differs by age, and which cell types undergo the phenomenon. Preclinical studies have demonstrated that subjects with obesity exhibit more senescence and more inflammatory markers and that senolytic drugs improve metabolism and life span.

Another trial, part of the NIH-funded Molecular Transducers of Physical Activity Consortium (MoTrPAC), aims to define how biological response to physical activity improves and preserves health. 

In Cedars-Sinai’s new physiology lab, Musi’s clinical trial will compare sedentary participants assigned to a randomized exercise program (either aerobic exercise or resistance training) with a highly active group that includes people who do each type of exercise. By analyzing functional measures and blood, muscle and adipose tissue, investigators will construct molecular maps of genes, proteins and enzymes in flux.

"Virtually every aspect of prominent diseases can be improved by exercise, but we don’t know how exercise works from a biological standpoint," Musi says. "Identifying these biomarkers will help tailor interventions to benefit each individual and people with disability who cannot exercise."

Additionally, Gonzales continues to analyze data from a clinical trial into senolytics as a therapy for Alzheimer’s disease. In a 2023 Nature Medicine paper, she published results of a trial that found D+Q was safe and dasatinib penetrated the central nervous system.

Another study, led by Espinoza and Musi, examines how the diabetes drug metformin might affect molecular and cellular mechanisms that underlie aging, including epigenetic modifications, cellular senescence and mitochondrial function. Observational studies have shown that diabetes patients on the medication have reduced onset of age-related diseases such as dementia and cardiovascular disease, but no clinical trial has yet focused on aging outcomes.

In collaboration with experts at the Cedars-Sinai Human Microbiome Research Institute, Espinoza and Musi hope to expand the study to examine the effect of metformin on biomarkers of Alzheimer’s disease and reveal how metformin affects the gut microbiome in the context of aging.

Read: Age: A Biological Guide to Longevity

Forging New Paths

Research on uncovering aging mechanisms is increasing, but the U.S. healthcare system still falls short on doctors who can provide geriatric care. Estimates predict a shortage of almost 27,000 geriatricians in 2025, according to the Health Resources and Services Administration.

Aging experts emphasize the importance of training the next generation of physicians on how age affects functional health so they can better help patients avoid worsening medical complications. Cedars-Sinai’s Center on Translational Geroscience will be an education hub for medical residents, graduate students and postdoctoral fellows. In fact, Cedars-Sinai is set to launch a new geriatric medicine fellowship in 2024, in partnership with UCLA.

"We want to try to secure the future of this field," said Espinoza, who co-leads the NIH-funded Geroscience Education and Training Network. "If we do discover therapies that effectively target health and function with aging, clinicians need to understand how to use them and which patients might benefit."

Further investigation in large, diverse populations could yield personalized therapies that protect function among even the most vulnerable patients. The aim is to help older adults live well—not just longer—with fewer injuries, disabilities, physical and mental illnesses, and medication side effects.

Musi predicts an explosion of advances and innovations in the aging field within the next two to three decades. However, treating age as an independent risk factor will necessitate shifts in trial design and endpoints to measure success. It also requires a critical overhaul of federal regulatory pathways. Currently, the FDA requires medications to be tested and approved for specific conditions or indicators, and aging is considered a natural process that doesn’t qualify as a disease state.

Scientists, regulators and lawmakers are debating whether that stance should shift, with Congress recently pushing the FDA to redefine its rules, according to the American Federation for Aging Research. Stakeholders recognize the urgency.

"We’re all aging; accelerated interventions could impact very important parameters of health, like glucose tolerance, insulin resistance, physical function and an overall sense of wellbeing," Musi said. "Older adults should not be a burden but rather an engine for a healthy, happy society."

Read: The Age Gap

The promise of regenerative medicine is, in effect, to restore the body to a younger state. Major research at Cedars-Sinai explores whether stem cell therapy can heal age-related degenerative diseases or reverse their damage.

In 2019, immunologist Helen Goodridge, PhD, published a study in the journal Communications Biology demonstrating that in aged rodent models of neurodegeneration, bone marrow transplants from young mice preserved cognitive function. Since bone marrow transplants replace a body’s blood stem cells, the findings suggest that the blood system can regulate brain cell aging and cognitive function, said Goodridge, associate director of Discovery at Cedars-Sinai’s Board of Governors Regenerative Medicine Institute.

The work supports the development of technologies to implant patients with their own rejuvenated blood cells and strategies to rejuvenate the blood stem cells in place.

"The young blood cells did not enter the brain, and yet the brain got 'younger,'" she said. "These are not completely separate systems. It suggests that if we can rejuvenate the blood, it might be sufficient to rejuvenate the brain, as well."

Goodridge’s lab is currently studying how sex chromosomes and sex hormones impact immune cell aging and inflammation, and it is attempting to distinguish between protective and destructive immune cell responses in the context of neurodegeneration.

A deeper understanding of how to disrupt pathological aging cycles relies on multispecialty collaboration, Goodridge said.

"Many signals influence the communication between blood and brain and how it changes with age,” she continued. “We have to examine this crosstalk."

Research indicates that treatment with specialized cells derived from induced pluripotent stem cells, or iPSCs, could provide a benefit in aging-related conditions such as Alzheimer’s disease, Parkinson’s disease, cancer, cardiovascular disease and wound healing, said Dhruv Sareen, PhD, executive director of the Cedars-Sinai Biomanufacturing Center. The center’s main mission is to manufacture FDA-compliant, clinical-grade iPSCs for use in critical clinical trials.

"To draw an older adult’s blood and turn back the clock by reprogramming the cells to a point where they are akin to pluripotent embryonic cells is to reverse the process of aging at a genetic and epigenetic level," he said. "We’re reversing the aging phenomena in a petri dish with cells. Can we take the learnings from this process at a molecular level and translate that to slow down the aging process of an entire individual?"

With 95 million adults poised to be age 65 or older by 2060, the medical system is recognizing that disjointed, one-size-fits-all care leads to avoidable and missed conditions in older adults as well as unsustainable costs.

"We need clinical models that can keep up with the patient population and change to address their unique needs," said Sara Espinoza, MD, director of Cedars-Sinai’s Center for Translational Geroscience.

Cedars-Sinai is at the forefront of reconfiguring care for people over age 65, informed by growing awareness that aging is a compounding risk factor for health and health span. The Age-Friendly Health System initiative is a national movement from the Institute for Healthcare Improvement and John A. Hartford Foundation to tailor screening and care for every older adult, focusing on medication safety, mobility, cognitive and mental health, and patients’ preferences regarding their care. Championed at Cedars-Sinai by Sonja Rosen, MD, chief of Geriatrics, the systemwide initiative is already reaping results.

This initiative could help hospitals bridge a growing gap. The number of U.S. geriatricians will fall from 8,220 to 7,580 by 2030, according to the American Geriatrics Society’s projections, as demand increases by 50%.

"The age-friendly model is a comprehensive framework for any physician, social worker or nurse caring for an older person," Rosen stressed. "While we need more people to train in geriatrics, most older adults’ healthcare won’t be provided by a geriatrician."

Cedars-Sinai’s flagship age-friendly program, the Geriatric Fracture Program, launched in 2018 for hospitalized patients with fractures who are age 65 and older. Led by medical director Carol Lin, MD, and Kathleen Breda, NP, the program’s multidisciplinary team evaluates and targets bone strength, gait, medications and other frequently overlooked physiological concerns that can cause falls, brain injuries and repeat fractures in older adults.

Studies show the program significantly decreased older patients’ length of hospitalization, reduced costs and improved rates of follow-up bone care. The program has become a national model of co-managed orthogeriatric care, in partnership with the general Geriatrics Program at Cedars-Sinai, which also supplements outpatient dementia and fall consults.

Another effort, Leverage Exercise to Age in Place (LEAP), is an exercise program that combats both a fear of falls and loneliness among older adults. LEAP, helmed by geriatrician Allison Mays, MD, is quickly proving itself as a fall-reduction strategy—lowering estimated monthly falls among virtual participants by 53% over six months. Classes teach age-appropriate exercise that incorporates balance and weight training. Paired workouts boost social connection and were proven to curb loneliness and isolation over six months.

Cedars-Sinai’s newly accredited geriatric emergency department, the Barry and Rena Plost Senior Emergency Center, seeks to improve emergency care for patients over age 65, who are three times as likely as those under 30 to return within 72 hours. Under Sam Torbati, MD, who holds the Levin/Gordon Chair in Emergency Medicine in honor of Joel M. Geiderman, MD, medical staff are trained to screen for, prevent or manage common geriatric syndromes (including delirium); reduce internal catheterization and patient restraints; and increase outpatient physical therapy, home health, or geriatric referrals. Caregivers partner with social workers and navigators to support social and behavioral needs, such as nutrition, depression or end-of-life wishes.

"A person doesn’t have to live to 100 to live well," Rosen said. "Age-friendly care is about increasing quality of life."

Age-related damage to protein folding and cellular energy make the aging brain vulnerable to Alzheimer’s disease. Research now points to a wide range of additional risk factors, offering a clearer picture of who might develop dementia as they age and suggesting how providers can lower predisposition.

Neurologists and geriatricians at Cedars-Sinai’s Bernard and Maxine Platzer Lynn Family Memory and Healthy Aging Program are leveraging new research insights into personalized preventive action—starting with education.

"Memory problems are not inevitable," emphasized the program’s director, Zaldy Tan, MD, who is also medical director of the Jona Goldrich Center for Alzheimer’s and Memory Disorders and holds the Carmen and Louis Warschaw Chari in Neurology." The first step is taking people out of this mindset that there’s nothing they can do."

Prevention is more crucial than ever: The number of patients with Alzheimer’s disease in the U.S. is expected to more than double to a staggering 14 million by 2060. The neurodegenerative disease is the fifth-highest cause of death for older adults in the U.S., according to the Centers for Disease Control and Prevention, and unlike cancer, deaths due to Alzheimer’s are rising.

The program's specialists measure each patient’s susceptibility to dementia. They consider patients' genetics, harmful exposures (including environmental pollution) and certain modifiable components, which the team characterizes with validated scales.

Hypertension in middle age strains the brain, which can cause dementia if left uncontrolled over one to two decades. Smoking, high stress and poor nutrition also influence both cardiovascular health and memory. To protect the brain and heart, neurologists champion the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet, which is high in fish, leafy vegetables, fruits, nuts and grains.

Regular social and physical activity can keep cognition sharp, as can intellectual stimulation, which should continue into professional retirement. Dementia experts recommend seven to eight hours of high-quality sleep every night, as well.

"Maintaining brain health involves the entire body," Tan said.

Genes are just one piece of a person’s cumulative brain health. A preventive strategy can even empower those with a family history of Alzheimer’s disease or early signs of neurological changes, potentially extending cognitive ability.

"We can give people agency by educating them on their individual dementia risks and the difference they can make with lifestyle changes, such as exercise," said Cedars-Sinai neurologist Sarah Kremen, MD. "You can save memory the way you do money: Save a little bit, and then look at how it adds up down the line."

Program neurologists are developing research protocols to monitor how interventions based on personalized risk profiling can impact the dementia risk of a healthy cohort. Studies could eventually integrate electronic health records and computational biomedicine to identify the best candidates, and wearables could track patient progress in sleep quality, heart rate and other related measures over time.

Additionally, leaders hope collaborations with community-based organizations will bring tailored preventive care to populations that historically have lacked access to this type of care and further inform their work.

"One of the greatest American health fears is Alzheimer’s disease, because it’s devastating," Tan said. "You can lose your independence, the memories you spent all your life making and nurturing, your opinions, and your talents—the things that make us truly unique."