Targeting the Biology of Aging is a New Era in the Treatment of Age-Related Disease
The editorial here is focused on Alzheimer's disease specifically, but the sentiments expressed apply equally to all age-related diseases. We are entering a new era, in which the research and development community stops trying to treat the symptoms of age-related disease and increasingly focuses on causes of age-related diseases. These conditions are in no way separate from the underlying mechanisms of aging: every age related disease is a manifestation of aging, and a consequence of underlying processes of aging that can be targeted, slowed, reversed. While advocates for aging research have been saying this for decades, the broader research community is now increasingly adopting this view. The future is bright!
Alzheimer's disease (AD) is characterized by senile plaques comprising β-amyloid (Aβ) proteins and neurofibrillary tangles formed by hyperphosphorylated tau aggregates. Massive efforts and resources have been poured into interventions aimed at removing or decreasing the production of Aβ. Until recently, amyloid and tau have been the focus of most drugs in development for AD. Beyond the accumulation of plaques and tangles, numerous processes go awry with aging that contribute to, or exacerbate, the pathology and progression of AD, including inflammation, impaired proteostasis, vascular dysfunction, mitochondrial/metabolic dysfunction, epigenetic dysregulation, and synaptic dysfunction. Thus, a combination of drugs to address many of these defects may be necessary to effectively treat AD. In recent years, an increasing number of drugs targeting these biological processes have emerged in the drug development pipeline for AD.
Currently, there are 143 agents in clinical trials for AD, of which 119 agents are disease-modifying agents. Of the disease-modifying agents, there are now more agents in AD clinical trials that are targeting inflammation (23; 19.3%) than amyloid (20; 16.8%) or tau (13; 10.9%). Inflammation is a major hallmark of aging, and chronic systemic inflammation is associated with brain volume shrinkage and impaired cognitive functions. While broad-spectrum anti-inflammatory drugs have failed to improve cognitive outcomes in AD patients, recent efforts have targeted specific aspects of inflammation that are harmful to the brain while sparing normal immune function. For example, senescent cells are thought to fuel age-related pathologies by evading cell death while continuing to release proinflammatory cytokines and chemokines to damage the surrounding tissue. Senolytic drugs can selectively induce apoptosis of these senescent cells, and there are currently 3 phase II clinical trials underway to test a senolytic combination of dasatinib (tyrosine kinase inhibitor) and quercetin (flavonoid) in mild cognitive impairment or early-stage AD.
Between the breadth of new drug targets under investigation that address the biology of aging, the rapid development and validation of new biomarkers, and the improved design and rigor of clinical trials, we are in a new era of Alzheimer's research and drug development. Given the multifaceted nature of AD pathogenesis and progression, and the many biological processes that become impaired with aging, it is unlikely that drugs addressing a single target will have enough efficacy in treating AD in a clinically meaningful manner. However, if incremental benefits are observed with some agents, combination trials should be considered. Combination therapies are the standard of care for many diseases of aging, including cancer and cardiovascular diseases, and will likely be necessary to successfully treat AD.