What to Expect in Aging

Everything we know about the way in which people fall apart with age is based on what happened in the past. The research community has access to centuries of good epidemiological data to demonstrate what to expect in old age both with and without modern medicine. Though when you stop to think about the old today, bear in mind that the oldest old spent most of their old age in a time prior to genetic testing, highly effective heart therapies, and many other developments of the past twenty years. Those who are merely elderly still lived half their lives in a medical environment that would appear extremely primitive to anyone forced to cope with it today. We don't tend to think of the period from the 1940s to the 1960s as a backwards era of low-tech medicine, as little separates us culturally from those years, but the widely available medicine of the time was indeed lacking in comparison to today's technology.

Life expectancy is an odd and often misunderstood measure. It doesn't predict future life spans, but rather is a statistical measure of the average life span of a given birth year cohort if they relived the same life history as did the present population of old people. That means the same technologies, the same economic circumstances, the same pace of progress, and so forth. Obviously that won't happen: life expectancy is a useful statistical measure for comparing progress in medicine from year to year, and it does keep on going up, but it isn't a useful tool to inform you of how long you will live. That timeline remains to be determined, and we live in a time of very rapid improvement in biotechnology.

At the best of times there is a decade of lag between laboratory demonstrations and widespread availability in the clinic, and the present state of regulation is far from the best of times. There is a growing disconnect between the accelerating progress of cellular biotechnology and the ever heavier ball and chain shackled to clinical implementation of that research. The gap is widening now, but I think that in the future medical tourism and competition between regulatory regions will overcome this issue: there will be a sudden flood of pent up technology over a fairly short period of time, but who knows when the dam will finally break. The costs of medical development are falling to ever smaller fractions of the present cost of regulatory compliance: if development to the point of practical and reasonably safe usability costs $50 million while compliance costs $500 million, and that isn't too far from the actual state of affairs, then something has to give.

The modern upward trend in adult life expectancy has spanned centuries, created first by control over sanitation and infectious disease, and later by increasingly effective treatments for age-related conditions. We should not expect this to continue as it has been, however. This decade and the opening years of the next are an important transitional period, a shift between (a) the past age in which no attempt was made to treat the causes of aging as a medical condition and (b) the new era in which researchers are focused on aging itself rather than merely patching over its consequences. We should expect a great difference in the trendline of human longevity in the decades ahead precisely because there is a great difference between trying to treat aging and not trying to treat aging.

Thus this paper is not a roadmap for the future of those in their 30s and 40s today. Rather it is a look back at the results of the past for those who are old today:

Age-Related Variation in Health Status after Age 60

Disability, functionality, and morbidity are often used to describe the health of the elderly. Although particularly important when planning health and social services, knowledge about their distribution and aggregation at different ages is limited. The older population consists of an extremely heterogeneous group of persons; the older the age group, the greater the variation found in cognition, physical and sensory function, and social engagement, to mention just a few examples.

We aim to characterize the variation of health status in 3080 adults 60+ living in Sweden between 2001 and 2004 and participating at the SNAC-K population-based cohort study using five indicators of health separately and in combination: number of chronic diseases, gait speed, Mini Mental State Examination (MMSE), disability in instrumental-activities of daily living (I-ADL), and in personal-ADL (P-ADL). Probability of multimorbidity and probability of slow gait speed were already above 60% and 20% among sexagenarians. Median MMSE and median I-ADL showed good performance range until age 84; median P-ADL was close to zero up to age 90. 30% of sexagenarians and 11% of septuagenarians had no morbidity and no impairment, 92% and 80% of them had no disability. 28% of octogenarians had multimorbidity but only 27% had some I-ADL disability. Among nonagenarians, 13% had severe disability and impaired functioning while 12% had multimorbidity and slow gait speed.

In this large cohort, we were able to capture the complexity and heterogeneity of health status in 60+ old adults. Until 80, most people do not have functional impairment or disability, despite the presence of morbidity or even multimorbidity. Disability is common only after age 90. The 80s are a transitional period when major health changes take place; often following the co-occurrence of more than one negative health event. If we consider good health as the absence of chronic diseases, functional impairment, and disability, good health is still the most prevalent pattern among sexagenarians. However, even among octogenarians, the most prevalent health state is characterized by presence of chronic disorders with impairment only in gait speed. In other words, morbidity and multimorbidity start early in late adulthood, but functional dependence becomes common only for people older than age 90.

Comments

This again, with the costs of compliance thing?

The rising costs are not because the clinical trials are onerous, it's because the drugs usually just suck. When a growing number of candidates fail the "Do we really want to foist this on the general public" test, it's not because the government is out to get drug companies (a quick glance at the TPP propositions shows how this is obviously false!), it's because the drugs either didn't work, caused too many serious side effects, or both. Again, the easy ones were already discovered.

There is simply a finite number of chemicals that can be beneficially administered to the human body, so of course they're going to be harder and harder to find (think mining for internet coins). New methods to find more are required, but we're stuck with conventional med-chem methods and limited simulations because the next generation of outright quantum simulation of physical chemistry won't get here until functional quantum computers do.

Don't lump the woes of traditional pharma with regenerative medicine, though. Regenerative medicine is still largely virgin soil.

Posted by: Slicer at March 6th, 2015 10:22 PM

@Slicer - Regulatory compliance does seem to be a problem. Just because it is not the only problem (drugs have side effects) doesn't mean that conversation about it is forbidden.

Why else has the current ruling party in the UK (The Conservatives) pledged to make clinical trials there less costly in a bid to attract biotech investment:

http://www.fiercebiotech.com/story/uk-open-biotech-business-and-mercks-buying/2014-11-20

Posted by: Jim at March 7th, 2015 11:14 PM

The regulatory environment in the UK is fundamentally different from the US. This is a nation with a National Health Service; the government is the entity buying the drugs.

It's not arbitrary hurdles that cost the bulk of the money, it's proving that the drugs actually work, unless you're suggesting that people should be allowed to sell drugs that haven't been proven to work well. A whole forty percent of drugs fail Phase 3; should they have been put on the market? (They failed because they didn't work well enough!)

There are a lot of cases that can be argued that the government doesn't need to be doing a few particular things or should go about its business quicker. But that's not what's being said here. What's being said here is that the FDA shouldn't exist because it forces drug manufacturers to spend a lot of money proving that their drugs are safe and effective (when 40% of them are not, the test was obviously necessary).

And if you go to a country without a functioning regulatory environment to receive unproven treatments, it's your funeral.

Posted by: Slicer at March 8th, 2015 1:15 AM

Yes drugs need to be proven to work, no one is trying to make any arguemenr aagainst that. But what about the case where sarcopenia isn't listed as a disease, and so companies cannot currently apply for IND for their compounds? Aging is in the same boat. There does seem to be a regulatory rachette in effect, as officals are only punished for failures, not rewarded for success. Given this incentive they will keep demanding more evidence up until the point that the cost of demanding this evidence in terms of being labled obstructionist matches the benefit they receive. This is countered somewhat by their desire to see new treatments. But people respond to economic incentives too.

Posted by: Jim at March 8th, 2015 10:05 AM

@Slicer

From a viewpoint of expected value (within an investment context), if approval costs are going up and failure rates remain high, there is less incentive and more risk for biotech and pharmaceutical companies to take chances/innovate.

The above comes at time when biotech and pharmaceuticals cost less to make (subtracting the cost of approval) and research is accelerating as previous data and experience is compounded. Businesses in these spaces should be failing smart, cheap, and fast.

Why then are approval costs rising and why haven't approval times decreased?

Government bodies like the FDA will not lower costs because they have no incentive to cut their own revenue (opposite is true). IMO they are parasites and it's a problem.

Posted by: johnathan at March 8th, 2015 11:51 AM

"and research is accelerating as previous data and experience is compounded"

No. Research processes may be upgraded through data and experience, but research can only decelerate as more compounds are discovered. Again, the analogies are readily available: mining for internet coins, Easter egg hunts, drilling for oil. There is only so much to be found, and finding more gets more difficult.

Similarly, drugs that work in lab conditions frequently turn out not to work in real life. These businesses aren't failing smart, cheap, and fast because the technology needed to adequately simulate a drug's behavior in actual people simply does not yet exist.

"Government bodies like the FDA will not lower costs because they have no incentive to cut their own revenue (opposite is true)."

The phrase "approval costs" implies that things work in a totally different way from reality. The cost of clinical trials is not some arbitrary number that the FDA just decides they will cost. The FDA's bureaucrats are government functionaries that get paid the same amount of money no matter what they do. The FDA's budget is set by the federal government. The costs of trials are the actual costs of conducting trials. Nobody at the FDA is going "Let's make Stage 3 trials cost more money!" although they might go "We need to make people start testing for X, Y, and Z".

There are probably good arguments that certain requirements of these trials are a bit too costly or not necessary, but, again, those arguments aren't being posted here.

Posted by: Slicer at March 8th, 2015 12:17 PM

"Research processes may be upgraded through data and experience, but research can only decelerate as more compounds are discovered."

This is only true of the micro (oil) not the macro (energy). Looking back, I think you are mostly right about drugs, but not medicine as a whole.

"These businesses aren't failing smart, cheap, and fast because the technology needed to adequately simulate a drug's behavior in actual people simply does not yet exist."

They wouldn't fail faster with less regulation?

Take for example that people are begging the FDA to allow ALS patients to take an exploratory drug: https://www.change.org/p/lisa-murkowski-fda-accelerated-approval-of-genervon-s-gm604-for-use-in-als <-"If the FDA does not grant Accelerated Approval, it will likely be 3 more years before patients are able to access this drug -- meaning that most people currently living with ALS will not live to see it reach market." Peasants crying for their elitist oppressors to set them free, no? Although, I wouldn't expect anything less from the agency that backs Oxycontin but "has not approved marijuana as a safe and effective drug for any indication". "The FDA's bureaucrats are government functionaries that get paid the same amount of money no matter what they do. The FDA's budget is set by the federal government." American politics is never this simple. The FDA asks for a budget. Federal agencies never ask for less, they never restructure, they never try to make things more efficient, and they almost never repeal previous rulings no matter how ridiculous. They always want more.

Posted by: johnathan at March 8th, 2015 4:26 PM

@ Slicer

Thanks for posting the sarcopenia link, I hadn't seen that drug before. Although, for future reference, those two links support Jim's point of view quite well:

First, the drug itself is NOT being marketed to treat sarcopenia- the company (Novartis) has had to find an INCREDIBLY rare disease (sporadic inclusion body myositis) which causes premature muscle wasting to target their drug to.

The problem is that there isn't a great, clear-cut regulatory framework for Novartis to produce a drug that treats muscle wasting in the elderly. There is, however, a clear-cut framework to make a drug that treats sarcopenia in the handful of patients with a clear, defined, clinical disease state, so they will make a drug to target them and hope to broaden the clinical base afterwards.

Also, looking through all of those studies where you imply the government views sarcopenia as a disease, that isn't exactly the case in those studies at all. They seek to make correlations useful for clinicians: e.g. if these patients have reduced muscle mass relative to their peers, how are their outcomes in our trials different. That does not, sadly, translate to the government viewing sarcopenia as a disease state that should be treated or reversed. Although, granted, those studies will likely form the basis for one day reclassifying sarcopenia as such.

Posted by: Esteban at March 8th, 2015 6:58 PM

John: I looked that one up. Why on Earth did they only give EIGHT PEOPLE (and four placebo controls) the drug in a Phase 2 clinical trial? GM604 has already been given an orphan drug classification and put on the fast track. There's a group of ALS researchers telling the FDA not to accelerate approval.

And yes, drugs put on the market will fail more quickly. In the bodies of people who thought they did work.

Esteban: The FDA specifically mentions sarcopenia on a page involving the investigation of new drugs. They also did a bunch of stuff over the past few years involving trying to figure out how to define it as a disease.

Yes, there are problems with the system. In particular, there seems to be a lot of left-hand/right-hand bullcrap between the NIH/NIA and the FDA. Somebody with a briefcase full of pink slips in one hand and an axe in the other probably needs to walk through and cut out some deadwood.

But remember, the pharma lobby is one of the most powerful in the US. If the FDA was really getting in the way of what they were doing, they'd be pushed out of the way by lawmakers rather quickly.

If you really want to see government obstructionism, take a look at how long it takes to get any GM food approved (the Arctic Apple took years longer than necessary, and the AquaBounty salmon is still in eternal limbo) or the CPSC's vindictive attitude towards small magnets.

Posted by: Slicer at March 8th, 2015 10:57 PM

Well people can argue that regulatory bodies are or are not limiting factors on the internet pretty much forever. I think the interesting thing will be if the UK can steal some of the research business from the US (or organically grow more of their own) by adopting a lighter regulatory touch.

The UK cannot at present match the US's deep and liquid capital markets, particularly the US's venture capital scene.

Posted by: Jim at March 9th, 2015 2:11 AM

@Slicer

Thanks for sharing. Federal agencies in the U.S. (and even the federal government) have a history of limiting freedom and abusing power. That is where a lot of my frustration comes from.

Anyway, you make some great points. Good conversation.

Posted by: johnathan at March 9th, 2015 9:15 AM

Post a comment; thoughtful, considered opinions are valued. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.