Near all work to date on the treatment of age-related disease has failed to consider or target underlying mechanisms of aging, the molecular damage that accumulates to cause pathology. It has instead involved one or another attempt to manipulate the complicated, disrrayed state of cellular metabolism in late stage disease, chasing proximate causes of pathology that are far downstream of the mechanisms of aging. This strategy has largely failed, and where it has succeeded has produced only modest benefits. Consider that statins, widely thought to be a major success in modern medicine, do no more than somewhat reduce and delay mortality due to atherosclerosis. They are not a cure. The mechanisms of aging are why age-related diseases such as atherosclerosis exist. They are the root cause of these diseases. Attempted therapies that continue to fail to target the mechanisms of aging will continue to fail to deliver meaningful benefits to patients. This must change.
Aging doesn’t kill people – diseases kill people. Right? In today’s world, and in a country like the United States, most people die of diseases such as heart attack and stroke, cancer, and Alzheimer’s. These diseases tend to be complex, challenging, difficult, and extremely ugly to experience. And they are by nature chronic, caused by multifactorial triggers and predispositions and lifestyle choices. What we are only now beginning to understand is that the diseases that ultimately kill us are inseparable from the aging process itself. Aging is the root cause. This means that studying these diseases without taking aging into account could be dangerously misleading … and worst of all, impede real progress.
Take Alzheimer’s disease. To truly treat a disease like Alzheimer’s, we would need to identify and understand the biological targets and mechanisms that trigger the beginning of the disease, allowing us to intervene early – ideally, long before the onset of disease, to prevent any symptoms from happening. But in the case of diseases like Alzheimer’s, the huge problem is that we actually understand very little about those early targets and mechanisms. The biology underlying such diseases is incredibly complex. We aren’t sure what the cause is, we know for sure there isn’t only one target to hit, and all prior attempts to hit any targets at all have failed. When you start to think about how much of what we think we know about Alzheimer’s comes from very broken models – for example, mice, which don’t get Alzheimer’s naturally – it becomes totally obvious why we’re at a scientific stalemate in developing treatments for the disease, and that we’ve likely been coming at this from the wrong direction entirely.
The biggest risk factor for Alzheimer’s isn’t your APOE status; it’s your age. People in their twenties don’t get Alzheimer’s. But after you hit the age of 65, your risk of Alzheimer’s doubles every five years, with your risk reaching nearly one out of three by the time you’re 85. What if going after this one biggest risk factor is the best vector of attack? Maybe even the only way to truly address it? This isn’t about the vanity of staying younger, about holding on to your good looks or your ability to run an 8 minute mile. It’s about the only concrete possibility we have to cure these diseases. Instead of choosing targets for a single specific disease, i.e. a specific condition that arises in conjunction with aging, we can get out in front of disease by choosing targets that promote health. And we can identify these by looking at disease through the lens of the biology of aging.
Link: https://a16z.com/2020/10/07/aging-alzheimers-drug-discovery/