Integrated anti-aging strategy could reduce neurodegeneration

By Dr. Liji Thomas, MDReviewed by Lily Ramsey, LLMMar 11 2025

Understanding the link between aging and neurodegenerative diseases: insights into risks, research, and emerging therapies.

Study: Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances. Image Credit: Inside Creative House/Shutterstock.com

Globally, the population is aging at an unprecedented rate. Today, one billion people are aged 60 or older, a number expected to double by 2050. Aging is a key factor underlying neurodegenerative diseases (NDDs) and associated conditions, including vascular disease.

Introduction

The risk of developing NDDs, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), increases sharply after the age of 60-65. AD prevalence rises from 5% among individuals aged 65-74 to 13% in the following decade and reaches 33% after age 85.

Currently, 55 million people are affected by dementia, a number projected to grow to 78 million by 2030. Dementias rank as the second leading cause of disability-adjusted life years (DALYs), which include years lived with disability (YLDs) and years of life lost (YLLs). AD accounts for 60-80% of these cases.

Beyond the emotional and physical toll of caring for individuals with NDDs, the economic burden is expected to rise significantly.

The cost of dementia care alone is projected to increase tenfold, reaching $9.1 trillion between 2015 and 2050. Currently, there is no cure for NDDs, and ongoing research aims to develop therapies that can enhance cognitive and physical function or at least slow disease progression.

Aging and Neurodegenerative Diseases

A recent study in Signal Transduction and Targeted Therapy explores the role of aging in NDDs using a complex adaptive system (CAS) model, often described as a “network of networks.” This model suggests that the brain acts as the hub of an interconnected system, where disruptions due to aging lead to a decline in homeostasis and the onset of NDDs.

Aging introduces several biological changes that contribute to NDDs, including inefficient DNA repair, accumulated genetic mutations, protein buildup, impaired nutrient sensing, oxidative stress, epigenetic modifications, chronic inflammation (inflammaging), stem cell exhaustion, and mitochondrial dysfunction.

In the brain, additional aging-related factors include excessive activation of immune cells (glia) and abnormal neural circuit activity.

Neuronal mutations and epigenetic changes lead to the accumulation of toxic proteins such as amyloid-beta (Aβ), hyperphosphorylated tau, and α-synuclein (α-syn). These proteins trigger neuroinflammation, exacerbate mitochondrial dysfunction, and increase oxidative stress, further damaging neurons.

Senescent glial cells struggle to clear these toxic proteins, which contribute to chronic inflammation. A weakened blood-brain barrier (BBB) allows harmful substances to enter the brain, creating a cycle of inflammation and neuronal damage.

As neurons become increasingly vulnerable, structural and functional decline follows. Neurotransmitter levels drop, gray matter volume shrinks (particularly in regions responsible for executive functions), and white matter becomes porous, impairing neural connectivity.

The depletion of dopaminergic neurons affects motor control, sensory processing, and cognitive functions, further diminishing overall brain health.

Advances in Aging Research

Over the past 70 years, research has uncovered multiple aspects of neuronal aging, including the accumulation of mutations, oxidative stress, immune system decline, and the role of endogenous retroviruses (ERVs) in tissue aging.

Genetic studies have identified mutations such as AGE-1 and Daf-2 in Caenorhabditis elegans, which significantly extend lifespan, leading to clinical trials investigating metformin's potential in delaying aging.

Proteins like sirtuin 1 (SIRT1) and sirtuin 4 (SIRT4) have been linked to extended lifespans, and small molecules that activate SIRTs have demonstrated a 70% increase in yeast longevity. Rapamycin, which inhibits the mTOR pathway, has also shown promise in extending mammalian lifespan by promoting autophagy and reducing protein accumulation.

Other experimental anti-aging strategies include eliminating senescent cells, infusing young plasma, and conducting fecal microbiota transplants (FMT), with studies suggesting cognitive improvements in patients with mild cognitive impairment (MCI) and PD.

Additionally, biological aging can now be assessed using DNA methylation-based aging clocks, providing a more accurate measure of physiological aging compared to chronological age.

Integrated Anti-Aging Strategies for NDD Prevention

Given the complex interplay between aging and NDDs, a multi-faceted approach is required. The brain is intricately linked to other body systems, meaning that interventions targeting cardiovascular, hepatic, and immune health could mitigate NDD risk.

Enhancing cardiovascular function improves oxygen and nutrient delivery to the brain while maintaining gut health helps prevent toxic protein buildup and systemic inflammation.

Emerging research highlights the role of viral infections, such as SARS-CoV-2, in accelerating aging and increasing NDD risk in older adults. Therefore, preventive strategies that enhance immune function and reduce chronic inflammation are critical.

Promising Anti-Aging Therapies

Several potential interventions have been explored to slow or prevent NDDs:

• Blood-Derived Anti-Aging Molecules: These compounds promote neurogenesis, clear toxic proteins, preserve dopaminergic neurons, and improve motor function.
• Pharmacological Approaches: Drugs like metformin, GLP-1 receptor agonists, and senolytics (which remove senescent cells) have shown promise in preclinical trials.
• Biological Therapies: Techniques such as young plasma infusions, gut microbiome rejuvenation via FMT, and stem cell transplants may help counteract age-related decline.
• Targeted Pathway Modulation: Inhibiting the mTOR pathway with rapamycin or activating SIRT proteins may protect neurons by reducing unwanted protein accumulation and improving cellular resilience.
• Immunotherapies: Antibody-based treatments targeting misfolded proteins are being investigated in combination with proven anti-aging interventions.

Although some trials have yielded mixed results, ongoing research is refining these strategies to maximize their effectiveness. Larger, long-term studies are necessary to validate these approaches before clinical implementation.

Conclusion

Neurodegenerative diseases do not arise from a single molecular or cellular dysfunction but rather from an overarching imbalance in the body's complex adaptive systems. This underscores the need for integrated interventions that address multiple aging-related processes.

A comprehensive approach—including a healthy diet, regular physical activity, cognitive training, and anti-inflammatory strategies—can help mitigate inflammation, enhance cardiovascular and respiratory health, and slow neurodegeneration.

Ideally, these preventive measures would be combined with disease-specific treatments and management of coexisting conditions to create a holistic strategy for preventing, treating, and potentially reversing NDDs.