How would a clinical study of an anti-aging therapy work

Factual Questions
1

I’ve read lots of stories about advances in the lab that could result in medical technologies that can, to a degree, slow or reverse aging (either causing a compression of morbidity or increasing lifespan and/or healthspan). So how would a clinical study work?

Would you give one group a placebo and give the other the medicine, then do a biopsy of their cells, or measure how many diseases of old age they get over a set period like 2-5 years?

If technology comes along that can supposedly add 30 years of healthspan to a persons life how do you measure that in a clinical study which may only be a few months or years?

Added to that, some therapies claim to just delay aging diseases, some claim to reverse them. So how would the studies have to vary to incorporate that? One involving high risk people at risk of a disease, another for people who already have the disease to see if it causes remission?

2

How do you measure an aging treatment in a study of only a few months or years? Simple: You don’t. You measure it in a study that lasts decades. Yes, this is hard. So?

3

The Framingham Heart Study is one of the most well-known and influential longitudinal medical studies. It started in 1948, and has now enrolled grandchildren of the original participants.

There are other major longitudinal studies, including The Nurses’ Health Study.

These types of studies require commitment on the part of participants, and inevitably some people do drop out, but they ultimately are the only way to really determine long-term effects.

4

Pharmaceutical patents expire 20 years after filing, plus the higher costs in clinical trials to conduct a trial that long will reduce/eliminate incentives to create those kinds of drugs.

5

How long can a product be protected by “Patent Pending” - that is, application filed, but patent not issued?

Begun in 1932, the infamous Tuskegee Syphilis Study lasted until 1972 when a whistle blower brought it down. That was run by the US Public Health Service, for those interested.

But yes, an anti-aging treatment would have to be run at least 30 years, and some of those who involved would not get the treatment.

6

A possible approach would be to use a proxy for cellular aging. Telomere shortening is hypothesized to be decent proxy (if not actually directly involved in the aging process).

So minimally an intervention that is, in the short to moderate term, associated with a decreased rate of telomere shortening, and prolongs disease-free lifespan in shorter lived animal models, is a good candidate for longer term clinical studies, looking both at mortality rates and new onset of various morbidities typically associated with aging.

So far the best intervention to decrease the rate of telomere shortening seems to be regular exercise. Shocking I know.

mTOR inhibitors are getting some press on the drug side. And indeed the TOR proteins impact telomere length in animal models. FWIW I am very skeptical given that mTOR is also required to maintain and build muscle (and results from regular exercise) which is associated with delayed aging clinically.

7

I’m bumping this thread because it’s been in the back of my mind for a few months, and I kept meaning to go back and write a response. However, this is a topic where I have enough expertise to know exactly how much I don’t know. (If this was about longevity treatments for certain model organisms I could blather all day…) So, rather than blather inaccurately about FDA regulatory frameworks, I figured I’d post some good things I’ve read recently on the topic.

The crux of the problem, as the OP correctly surmises, is that any clinical trials are going to take decades to complete, and “less aging” is a poorly defined end point. As I understand it, the FDA isn’t even interested in treatments for aging (though that’s not an insurmountable barrier since anything worth calling a “treatment for aging” has got to put a pretty big dent in age-related disease and morbidity). That may change since there is strong interest in starting clinical trials to see whether metformin can prevent aging.

The 20-year patent life is another big issue. If a drug company wants to test and market a new anti aging treatment, for now they can start with shorter term trials to see whether the drug is useful for treating some particular disease. Since there is a lot of overlap between pathways that control aging and metabolism, there’s good reason to believe that many possible aging treatments will also directly treat metabolic syndrome, diabetes, or many other diseases.

In the near future, there may be sufficient knowledge of age-related biomarkers that can be used to test the effects of a drug in a clinical trial. We know of many cellular and systemic factors that both increase with age and contribute to further age-related dysfunctions. The biomarker approach has been taken before, with trials for cardiovascular drugs that used cholesterol levels as an endpoint, and (so far unsuccessful) trials for Alzheimer’s treatments that use reductions of amyloid levels as an endpoint. There’s a review of biomarkers, target pathways, and interventions here (getting this particular review off my to-read list reminded me about the post!)

On the regulatory side, the FDA can and has provided a period of exclusivity beyond the end of a patent. For example, Orphan Drug Exclusivity is granted for 7 years after FDA approval for treatments for rare diseases without effective treatments. That’s partially in recognition that it can take many years to find enough patients to accumulate a decent statistical sample. It’s conceivable that similar incentives could be given, by act of Congress, to companies developing new treatment for aging*. Off the top of my head, perhaps a drug company and the FDA decide that an X year stage III clinical trial is necessary, so the FDA grants an X-5 year exclusivity extension beyond the patent expiration.

*I bet it would be pretty easy to get overwhelming bi-partisan support for promising anti-aging treatments, given the age of the average Congresscritter…

8

Thank you for that article lazybratsche.

I notice right off that two highlighted possibilities are indeed protein restriction and mTOR inhibition (with the former supposed to be of impact via the latter).

Any thoughts that you have on how to square that with clinical data that demonstrates that exercise and higher protein inrake (both of which stimulate mTOR pathways is associated with less functional decline during aging, and fewer of the diseases of aging?

9

You could also make the argument that if you were to test a substance which reverses the aging process (gerontologists call this ‘rejuvenation’), you could get results more or less instantly. If I understand the literature right, reversal of the aging process has already been demonstrated in cardiovascular tissue in dogs subsequent to administration of Alagebrium. Results were somewhat disappointing in humans though.

10

I don’t have any specific thoughts, other than to wave my hand and say it’s complicated. In general, it’s too simplistic to talk about one particular pathway having one specific effect when globally upregulated or downregulated.

  1. A specific stimulus can upregulated a pathway in one tissue while downregulating it in another.
  2. One pathway can have different effects in different tissues.
  3. A pathway can have different effects depending on the levels or dynamics of activation (e.g. one big pulse of activation vs continual low level activation vs regular pulses of activation).

TOR is a particularly complicated example, since it’s a node in a lot of signaling networks. There are many known interactions with other major regulators of metabolism and aging like Insulin/IGF and AMPK (and when I pull up a review of TOR regulation, there’s direct interactions with the Hippo, Wnt, and Notch pathways…)

I see that those reviews of the effects of exercise on TOR pathway activity covers many of those complications: exercise activates TOR in muscle and brain, but inhibits in fat and liver, TOR activation is AKT-independent in skeletal muscle but AKT-dependent in heart muscle, etc.

To get back to the OP, these complications make it hard to predict whether any small molecule pharmaceutical can prevent aging. Systemic inhibition of a pathway will always have negative side effects, and there’s no general way to get a small molecule or biological to only go to a specific tissue.

11

Twins?

12

True but there’s lots of evidence to support the notion of a trade-off between growth and longevity: Smaller animals within a particular species generally live longer (Big mice die young but large animals live longer - PMC), short men live longer, despite having no reason to :slight_smile: (Shorter Men Live Longer: Association of Height with Longevity and FOXO3 Genotype in American Men of Japanese Ancestry), the average CFL player has a life expectancy of just 55 (http://www.theglobeandmail.com/sports/hockey/concussions/life-expectancy-of-55-shocks-cflers-into-push-for-safety/article1972521/), and Ecuadoreans with Laron dwarfism don’t appear to get cancer or diabetes (http://www.nytimes.com/2011/02/17/science/17longevity.html?_r=0).

13

A perfectly cromulent answer. :slight_smile:

Growth and metabolic rate both.

The fairly well established correlation of lower heart rate with longer life expectancy (both between and with species including humans) likely reflects that … along with higher parasympathetic tone being protective.

The role that the mTOR pathways have in that (and I can believe they are involved) almost have to be very complicated, a function of exactly when and where, not something that a pharmaceutical is likely to accomplish. Yet again though … amazingly regular activity and various dietary patterns do seem to.

Thanks for the links … as a short man (with a low resting heart rate even when not exercising regularly) I am pleased.