Much More than Just Loss of Mass is Involved in the Age-Related Decline of Muscle Function

It has been some years since sarcopenia was coined as a name for the characteristic loss of muscle mass and strength that occurs with aging, one of many attempts - some successful - to carve off an aspect of aging and obtain regulatory approval to work on treating it. It remains the case that making an official disease of sarcopenia is an ongoing process of lobbying with no end in sight, however. Without that blessing of the state there is no legal path to the translation of promising research into commercial clinical treatments, and thus far less incentive for the major funding sources to invest in any of the research needed to even get to the point at which commercial development is plausible.

In countries like the US only treatments for one of a list of defined diseases are considered for approval by the FDA, very much a case of all that is not permitted is forbidden. Even if sound and proven treatments exist and are widely used elsewhere in the world, people can be ruined financially and potentially go to jail for a long time for offering those treatments in the US. This was the case for first generation stem cell therapies for quite a number of years, for example. One of the large problems for the near future of longevity science as a whole is that aging itself is not considered a medical condition by the FDA and similar regulatory bodies. For so long as that is the case all meaningful early clinical development must occur in other regions of the world, and more importantly there will continue to be far less funding for research than might otherwise be the case.

Back to sarcopenia, however. There is indeed loss of muscle mass in aging, and this is a major cause of the frailty of later life. There is much more to the underlying processes than just a simple loss of mass, however. It is much more complex than that, as this review notes. The quoted portions are from the introduction and summary, and in between there is a more detailed overview of some of the mechanisms mentioned - it makes for interesting reading within the context that the practice of calorie restriction slows the progression of sarcopenia.

It is not just muscle mass: a review of muscle quality, composition and metabolism during ageing as determinants of muscle function and mobility in later life

Worldwide estimates predict 2 billion people will be aged over 65 years by 2050. A major current challenge is maintaining mobility and quality of life into old age. Impaired mobility is often a precursor of functional decline, disability and loss of independence. Sarcopenia which represents the age-related decline in muscle mass is a well-established factor associated with mobility limitations in older adults. However, there is now evidence that not only changes in muscle mass but other factors underpinning muscle quality including composition, metabolism, aerobic capacity, insulin resistance, fat infiltration, fibrosis and neural activation may also play a role in the decline in muscle function and impaired mobility associated with ageing. Importantly, changes in muscle quality may precede loss of muscle mass and therefore provide new opportunities for the assessment of muscle quality particularly in middle-aged adults who could benefit from interventions to improve muscle function.

Several longitudinal studies suggest that muscle mass alone cannot fully explain the loss of muscle strength and physical function in older adults. Estimates of the rate of change in muscle strength with age derived from a cross-sectional cohort have also been suggested to underestimate actual yearly changes in muscle strength. In the Health, Ageing, and Body Composition (Health ABC) study, the decline in muscle strength during ageing was reported to be two- to five fold greater than the loss of muscle mass in older adults aged 70-79 years over a 3-year follow-up period. Furthermore, there was wide inter-individual variability in changes in muscle cross-sectional area and muscle strength in older adults, such that muscle mass and muscle strength were well-preserved in some individuals but not others.

It will be important in future to better understand the main factors which underpin changes in muscle quality with age, which may well precede changes in muscle mass or be of greater functional significance in ageing muscles, with declining size. In addition, a universal consensus definition of muscle quality is necessary. Muscle quality is typically used to describe muscle strength or power per unit of muscle mass, therefore does not encompass muscle aerobic capacity which is closely associated with mobility and important for activities of daily living. Currently, there is a large gap in our knowledge on the primary determinants of muscle quality in middle-aged adults. The development of muscle quality assessment tools that encompass muscle quality and which are sensitive to small changes within muscle that precede a decline in muscle function would enable individuals to take preventative steps to maintain healthy muscle.

Comments

Reason, we can all tell that you're not fond of the unelected bureaucrats at the FDA. However, from a purely pragmatic point of view, wouldn't it be better to have the anti-aging experts *become*, or at the very least influence, the unelected bureaucrats (who are, themselves, slowly dying like the rest of us), rather than spending time ranting about them and wishing the FDA would disappear?

http://www.fda.gov/advisorycommittees/committeesmeetingmaterials/bloodvaccinesandotherbiologics/cellulartissueandgenetherapiesadvisorycommittee/ucm129401.htm

As part of the Food and Drug Administration's (FDA's) ongoing efforts to recruit qualified experts with minimal conflicts of interest who are interested in serving on FDA advisory committees, FDA is requesting nominations for members to serve on its advisory committees.

--> Current Number of Vacancies: 2 <-- Note, one or more vacancies may be in the nomination process or a final appointment may have been made. I'm seeing one "Neuroregeneration" and four "Regenerative Medicine" in this list already, which looks like an excellent start. And I know that the pharmaceutical lobby is somewhat overpowered, but Google's gotten itself involved with Calico; you'd think it wouldn't take much persuasion to provide a solid counterbalance.

Posted by: Slicer at December 5th, 2014 8:03 PM

The fact that aging isn't considered a disease isn't a problem. All therapies developed target some kind of malaise caused by the accumulating damage.

Posted by: Michael-2 at December 6th, 2014 1:48 AM

Slicer, working from within that system is worse than useless. That time would be much better spent elsewhere. I think Reason has some posts on that subject.

Posted by: Arren Brandt at December 7th, 2014 4:13 AM

Worse than useless to work with a regulatory body? Really? Which other country do you think will be better to market these therapies in, then? (This isn't entirely a rhetorical question)

Of these two approaches, which one do you think is likely to be more effective:

- Tilting at windmills hoping the FDA will simply go away (never mind that the FDA is widely supported and is the only thing currently stopping total, obvious snake oil from being sold as "anti-aging therapy"; seriously, opposing the FDA makes you look like a crank)
- Lobbying the government through the same methods everyone else does

Take the organic food lobby (please, someone take them!) They continuously manage to get respect from the federal government, including getting some types of bioengineered food left in limbo, even though the USDA's APHIS has made it fairly clear (in a recommendation that the Arctic Apple be approved for unregulated status) that everything the organic lobby says has absolutely no scientific basis whatsoever. How does this lobby do this? By being loud, obnoxious, and impossible to ignore.

Arren, I've read the posts, and they all seem to be that the FDA, and the government in general, is an irredeemably evil set of faceless bureaucrats. How much have those posts actually accomplished over the ~12 years he's been making them? Personally, I don't care if the FDA lunchroom serves up Girl Scout cookies made from real Girl Scouts with blended babies as a chaser; the government happens to be staffed entirely by mortal human beings who have the same slow-death pathology as the rest of us.

If people who don't want to die of old age wasted less time opposing strongly supported government agencies like the FDA and spent more time drumming up popular support among other people who don't want to die (a noticeable portion of the country has a strong anti-death stance, at least when it comes to themselves), their chances of dying of old age would be reduced.

Absolutely no advancement in science has been made by sitting around wishing things were different. Dealing with government agencies and society in general is different, but it follows the same fundamental principle. This is the world we were born into; deal with it or die.

To that end, did you gentlemen know that the NIA is accepting recommendations for its future policy direction? I wouldn't have known that reading THIS blog! http://grants.nih.gov/grants/guide/notice-files/NOT-AG-15-001.html This draft is *extremely* informative as to the government's policies and classifies aging as not a disease. If you want to offer evidence to them that it actually is, or want them to fund research into curing it anyway, this week would be an excellent time to offer recommendations.

I sent them a five-paragraph email suggesting that more money and time be put into researching the reversal of aging despite its political connotations, and I'm not even a professional. Shouldn't it behoove the professionals to use their credentials here? Shouldn't it behoove Reason, who appears to know at least some of the professionals personally, to get them to help?

Posted by: Slicer at December 7th, 2014 3:07 PM

I agree with Slicer. I have been bothered by your rants against the FDA before, but I have accepted it as your opinion. Although I have no direct control over the FDA, if I thought I needed needed control, why should I not form a group to lobby it like everyone else does. I appreciate the regulations that the FDA imposes because I have seen the effects of drugs like thalidomide on our society. Caution is not a bad thing. This is still my country an my government and I will do what I can to make sure it still works for us.

Posted by: Llewellyn Drake at December 7th, 2014 6:13 PM

It is simply incorrect to say that "aging itself is not considered a medical condition" and reflects the author's unfamiliarity with medical diagnoses. According to the International Classification of Disease (ICD-9-CM) that provides a system of diagnostic codes for classifying diseases, 797 is a billable diagnostic code that applies to "Frailty, Old age, Senescence, Senile asthenia, Senile debility and Senile exhaustion". The corresponding code in ICD-10 is R54. If this is not a disease or a "medical condition" then what is it? All that physicians have to do is to code appropriately those medical conditions that they see, diagnose and treat. Whether they are doing this or not is another matter, probably worth looking into.

Posted by: Andrius Baskys, MD, PhD at December 7th, 2014 6:24 PM

@Slicer, @Llewellyn Drake: Lobbying the FDA is an ongoing, perpetual drain on resources and is actively carried out by many groups, some of which have very large budgets devoted to nothing but lobbying. Yet the cost of trials and number of approved new technologies each year continue to move in the wrong direction. That suggests that this isn't a useful course of action, even setting aside my biases regarding big government and lack of accountability.

When you engage with a system you approve it, you support it, you legitimize it. That is exactly the opposite of what must happen if there is to be sweeping reform.

There is a very viable alternative, which is for researchers to primarily focus on development for clinical markets outside the US, and indeed that has been demonstrated by the recent history of stem cell medicine. The FDA tends to cave when a given medical technology is widespread elsewhere, since that situation results in political pressure, unlike the situation in which a domestic line of research is forever in trials and not in the press. With medical tourism in the mix eventually the FDA becomes irrelevant and must reform or atrophy. That is the efficient way to go about changing the world: regulatory arbitrage, where the money and effort goes towards actually building new technology rather than ineffectually begging for permission.

@Andrius Baskys: I'm not up to speed on how various industry-adopted coding systems like the one you mention are employed by the FDA versus by the penumbra of off-label applications and so forth. I do know that the FDA won't approve a treatment for aging at the present time, but would rather want it sidetracked into an approval process for one specific late stage condition of aging. This has consequences for the direction of research - e.g. when it was still possible that sirtuins might be slightly useful the main thrust of development was for diabetes treatment. That would naturally favor ending up with a diabetes treatment rather than a actual treatment focused on aging: you get to where you are going, and it is far from the case that a treatment so sidelined would still be useful for aging.

Some people in the community place most of their hopes of regulatory bypass on off-label uses of future rejuvenation treatments following narrow approval for one specific condition of aging via the present horrid approval system. Though the codes are certainly a lever that can be used in ongoing lobbying for a less horrid system once meaningful treatments for aging exist.

Posted by: Reason at December 7th, 2014 7:00 PM

Dr. Baskys, is it possible for a proposed treatment to have an FDA-approved endpoint of ameliorating 797/R54?

Posted by: Slicer at December 7th, 2014 7:02 PM

I don't think even off-label applications are that necessary. The categories of diseases quite often overlap so it's likely treating on path affects multiple diseases.

Treating aging as a disease only appreciably affects the traditional Gerontological/messing with metabolism approach. It's not something that there needs to be a whole of concern about.

Posted by: Michael-2 at December 7th, 2014 11:35 PM

Slicer is right. I'm going to send them an email, and everyone else should too. And Reason should overcome his biases and post the details on his blog.

I don't disagree with the need for medical tourism, but anything we can do to shift the NIA or FDA towards anti-aging therapies will make a huge difference in funding.

Criticising the FDA is useful. I used to be a huge supporter of strongly regulating the medical industry. But I've come to realise that false negatives are more dangerous than false positives, and that the amount of money people waste on snake-oil is less than the amount of money people waste testing things thoroughly to make sure they aren't snake-oil.
Every ineffective drug that is developed still has to be trialed, and still has the same costs even if it fails, and you the consumer will still have to pay for the ineffective drug's development when it is passed on as higher costs for the effective medicines you buy. So there is little difference to your wallet if they accidentally let the ineffective drug through.

@Llewellyn Drake: "I appreciate the regulations that the FDA imposes because I have seen the effects of drugs like thalidomide on our society."
Yes, but you CAN'T SEE the effects of the LACK OF DRUGS that the FDA regulations caused. Millions of people die from the lack of drugs, and millions more suffer.
Thalidomide is a bad example because it was for pregnant women (and for interfering with their pregnancy). Normally there is nowhere near that level of risk.
We need an FDA that balances the number of people who will die from not allowing medicines, with the number of people who will die from bad medicines, instead of only focusing on one side like it does now.

"Caution is not a bad thing." - Oh yes it is! Caution is a very dangerous thing. Caution is destroying the world. Caution is stopping us from using nuclear energy to solve global warming and the world's energy crisis for the next 500 years. Caution is stopping us from using genetic engineering. Caution is stopping us from curing aging. Caution has dramatically slowed drug development.

"This is still my country and my government" - No, it is now colonised by Mexico and Africa. Your country is long gone. The government and DOJ's number one goal is dispossessing people like you who created the country, inciting racist violence against you, and replacing you with foreigners.

But I agree we should all make a submission. I'm not even an American, but I'm going to make a submission.

Posted by: Carl at December 8th, 2014 7:48 AM

The Flash season 1 episode 7 has a positive mention of curing aging. It talks about it being more important and feeling better to do than stopping crime. And suggests it has to be done quickly. And that it's not just about you. With the hero agreeing.

I hope that indicates a change in popular culture.

Posted by: Carl at December 8th, 2014 1:01 PM

I agree with Reason. This is an economic/political theory issue more than anything and the FDA *should* self correct as research and treatment continues to accelerate on the global market.

Posted by: johnathan at December 8th, 2014 1:46 PM

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