Effective Treatment of Alzheimer's Disease Requires Targeting the Mechanisms of Aging

These days, an ever larger fraction of the research community is waking to the idea that the effective treatment of age-related disease requires approaches that target the mechanisms of aging. This is a good thing, as it begins to narrow the scope of advocacy within the research community to the task of steering scientists towards better rather than worse ways of going about targeting the mechanisms of aging. It remains the case that most of the better supported lines of work related to aging are, in effect, very challenging ways to produce only small benefits at the end of the day - most researchers are working on methods of slightly slowing aging rather than methods of outright rejuvenation.

Attempts to develop calorie restriction mimetics or other therapies capable of upregulating stress responses and cellular maintenance processes are a good example of the type, and they are much on display in this open access paper (currently available in PDF format only), alongside other targets that, while not being root causes of aging, are thought of as being significant enough in the progression of disease to merit effort. While goals such as suppression of chronic inflammation and overriding the dysfunction of vascular cells are seductive, in the sense that many near-term approaches are viable, this sort of work still leaves the underlying causes of aging untouched, and is thus limited in the benefits it can provide.

Geroscience is a multidisciplinary field that examines the relationship between biological aging and age-related diseases. The Trans-NIH Geroscience Interest Group Summit discussed 7 processes that contribute to biological aging: macromolecular damage, epigenetic changes, inflammation, adaptation to stress, and impairments in proteostasis, stem cell regeneration, and metabolism. Intriguingly, these 7 processes are highly intertwined with one another. Thus, targeting the common biological processes of aging may be an effective approach to developing therapies to prevent or delay age-related diseases.

Biological aging is the leading risk factor for the major debilitating chronic diseases of old age that cause morbidity and mortality, including Alzheimer's disease (AD) and other dementias. Drugs that treat fundamental biological mechanisms of aging have been proposed to be useful for most prevalent chronic diseases of aging. In fact, many repurposed drugs are used to treat other age-related diseases. Despite over 75 years of accumulated research on biological aging, the current drug development pipeline is dominated by therapeutics targeting amyloid-β and tau, and there has been proportionately less translation of biological gerontology into our efforts to develop drugs for AD.

Nevertheless, aging biology provides numerous novel targets for new drug development for AD. Because of the multifaceted nature of biological aging, it is unlikely that drugs addressing a single target will be very successful in effectively treating AD. Nevertheless, single drug clinical trials may be needed to demonstrate incremental benefits, even if modest, before combination trials can be pursued. As interventions that target one aberrant system tend to also attenuate others, ultimately, combination therapies that target multiple age-related dysfunctions may produce synergistic activities.

Combination therapies are already the standard of care for other diseases of aging, including heart disease, cancers, and hypertension, and will likely be necessary in treating AD and other dementias. And because the same biological aging mechanisms underpin the common diseases of aging, repurposing drugs already on the market is a rational strategy for testing new therapies for AD and related dementias, including the sporadic forms of frontotemporal dementia and vascular dementia. Novel therapeutics for new and relevant targets will clearly also be needed.

In addition to combination therapies, addressing the multifaceted nature of the relationship between biological aging and AD with drugs possessing pleiotropic effects (simultaneously producing more than one effect) will be advantageous. Many effective drugs act on multiple targets while single-targeted approaches seldom progress to the final stages of clinical trials. For example, statins are widely used to lower cholesterol levels in patients with dyslipidemia, but statins also have pleiotropic effects that are independent of their effects on cholesterol, including improved endothelial function, inhibition of vascular inflammation, stabilization of atherosclerotic plaques, and immunomodulation. To effectively treat AD, pleiotropic drugs may need to hit the right nodes of relevant biological networks affected by aging such that they positively influence those networks and interconnected pathways.

Finally, a parsimonious approach to drug discovery and development with regard to translating knowledge from biological aging to AD is needed. For example, due to the plethora of misfolded proteins that accumulate with aging in the brain, biologics that attempt to address a single misfolded protein may be far less efficacious than drugs that enhance autophagy and clearance of all misfolded proteins. Similarly, age-related inflammation, vascular disease, epigenetic dysregulation, mitochondrial/metabolic dysfunction, and synaptic failure may be upstream causes of neuronal dysfunction and death leading to the classic pathologic hallmarks that have been historically among the first drug targets in AD. A better understanding and translation of the systemic, cellular, and molecular processes of biological aging that precede and increase vulnerability to AD will help identify new strategies and therapeutic targets for drug discovery and development.

Link: https://doi.org/10.1212/WNL.0000000000006745

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