LONGECITY

One of the important points made by advocates for the treatment of aging is that one cannot distinguish between aging and age-related disease. They are one and the same. There is no magical state of "healthy aging" in which one doesn't suffer eventual disease. A decline of function in aging that does not rise to the level required to call it a disease is the subclinical stage of that disease; all the same damage has taken place under the hood, just less of it. Conversely, an age-related disease is just another facet of aging, a collection of damage and consequences of damage that becomes sizable enough to reach the definition of disease. Whether or not any specific age-related dysfunction is called a disease is just a matter of whether the degree of dysfunction is on one side or another of an arbitrary line drawn in the sand.

The authors of today's open access paper take this point and then build on it to suggest that the most robust age-slowing approaches demonstrated in animal models should be tested more rigorously in patients with common, hard-to-treat conditions such as Alzheimer's disease. The approaches with the best data include calorie restriction and all of the calorie restriction mimetic interventions that seek to replicate some part of the sweeping cellular reaction to a reduced intake of calories. Interestingly, this hasn't been well tested in Alzheimer's patients. Perhaps it should be, even given that the research community expects effects on aging to be lower in long-lived species than in short-lived species. While calorie restriction extends mouse life span by as much as 40%, it certainly doesn't do that well in humans. The actual number has yet to be established, but it would be surprising to see that the effect of long-term calorie restriction or equivalent intermittent fasting in humans is larger than a few years of additional life span.

Aging as a target for the prevention and treatment of Alzheimer's disease

Alzheimer's disease (AD), the most common etiology of dementia in older adults, is projected to double in prevalence over the next few decades. Current treatments for AD manage symptoms or slow progressive decline, but are accompanied by significant inconvenience, risk, and cost. Thus, a better understanding of the risk factors and pathophysiology of AD is needed to develop novel prevention and treatment strategies.

While a mayfly has a lifespan of one day, an elephant's lifespan may exceed 100 years. Clearly, lifespan and aging are biological traits regulated by genetics and molecular signaling pathways - that may be exploited as a therapeutic target. Aging, however, is not recognized as a disease by the U.S. Food and Drug Administration. Thus, there are no FDA-approved treatments specifically for aging. Aging, however, is the most important risk factor for multiple diseases, including dementia and AD. As molecular mechanisms regulating aging are coming to light and signaling pathways uncovered, novel therapeutic targets present an alternative approach: instead of targeting one disease at a time - leading to the inconvenience, cost, and risk of polypharmacy - targeting aging directly may prevent or slow multiple age-related diseases. CR may be a promising preventive or therapeutic option for individuals at risk for AD or already within the AD spectrum. However, current data are limited and human studies are scarce. Additional preclinical and human studies are now warranted to discover the pathways regulated by CR and to identify pharmacophores that mimic the beneficial effects of CR.

Hypotheses linking CR and weight loss to alterations in biomarkers of aging and AD may suggest novel treatment targets and strategies-and not just for AD. Newly discovered therapies may be safe and effective for prevention and/or as an adjunct to FDA-approved treatments for individuals in the AD spectrum. Prevention and treatment strategies targeting aging may be safer and more effective than the currently available treatments targeting more downstream pathways. While several studies are in progress (listed above), more are needed. In the meantime, AD trials should consider including biomarkers of aging and aging studies should include AD biomarkers.