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Aging As a Disease

I’ve mentioned numerous times around here that therapies directed against aging in general have a rough regulatory outlook. The FDA, in general, has not considered aging a disease by itself, but rather the baseline against which disease (increasingly) appears. This has meant that companies with ideas for anti-aging therapies have had to work them into other frameworks – diabetes, osteoporosis, what have you – in order to get clinical data that the agency will be able to work with.
Now, according to Nature News, the group that’s testing metformin for a variety of effects in elderly patients is going to meet with the FDA to address just this issue:

Barzilai and other researchers plan to test that notion in a clinical trial called Targeting Aging with Metformin, or TAME. They will give the drug metformin to thousands of people who already have one or two of three conditions — cancer, heart disease or cognitive impairment — or are at risk of them. People with type 2 diabetes cannot be enrolled because metformin is already used to treat that disease. The participants will then be monitored to see whether the medication forestalls the illnesses they do not already have, as well as diabetes and death.
On 24 June, researchers will try to convince FDA officials that if the trial succeeds, they will have proved that a drug can delay ageing. That would set a precedent that ageing is a disorder that can be treated with medicines, and perhaps spur progress and funding for ageing research.
During a meeting on 27 May at the US National Institute on Aging (NIA) in Bethesda, Maryland, Robert Temple, deputy director for clinical science at the FDA’s Center for Drug Evaluation and Research, indicated that the agency is open to the idea.

Metformin and rapamycin are two of the compounds that would fit this way of thinking, and there will surely be more. Let’s face it – any other syndrome that caused the sorts of effects that age does on our bodies would be considered a plague. To quote Martin Amis’s lead character in Money, who’s thinking about an actress he’s casting in a movie who “time had been kind to”, he goes on to note that “Over the passing years, time had been cruel to nearly everybody else. Time had been wanton, virulent and spiteful. Time had put the boot in.” It sure does.
But we’re used to it, and it happens to everyone, and it happens slowly. Does it have to be that way? The history of medicine is a refusal to play the cards that we’ve been dealt, and there’s no reason to stop now.

43 comments on “Aging As a Disease”

  1. David says:

    As a general rule, if I see in an obituary the age of over, say 85, my mind lists the cause of death as age, almost regardless of actual circumstances.

  2. anon says:

    If a drug could prolong ageing, and if it’s prolonged long enough, most people will die of cancer. I’d prefer to die of old age than cancer.

  3. Mark Thorson says:

    Losartan should be added to that list. In addition to its role as an ARB, it’s a strong up-regulator of GTPCH1 activity. GTPCH1 performs the rate-limiting step in tetrahydrobiopterin (BH4) synthesis. There’s a steep age-related decline in BH4 which may be responsible for some of the diseases of old age. BH4 is an essential cofactor for endothelial nitric oxide synthase, and this decline may cause the age-related increase in endothelial dysfunction. Endothelial dysfunction is generally accepted as the initial event leading to atherosclerosis, and a strong case can be made that it also causes type 2 diabetes. There’s also a growing body of evidence implicating it in sporadic Alzheimer’s disease.
    If we start looking for anti-aging drugs, losartan should be in the trials.

  4. pharmacology rules says:

    MT–i would think the losartan data could be there already. Was there prolonged life in the carc studies? The clinical experience in millions of patients could provide a hint.

  5. Lane Simonian says:

    Some studies for metformin indicate that it may actually increase cognitive decline in some elderly individuals. One explanation for this is metformin’s increased activation of AMPK is neurodestructive rather than neuroprotective in cases of oxidative stress.
    AMP-activated protein kinase: a potential player in Alzheimer’s disease.
    Salminen A1, Kaarniranta K, Haapasalo A, Soininen H, Hiltunen M.
    In regards to BH4, its oxidation likely does play a role in the progression of Alzheimer’s disease.
    http://link.springer.com/article/10.1007/s11064-006-9201-0

  6. Anonymous says:

    Losartan >>> NO? Then what about organic nitrates? They have form in life extension in rodents, after all…..

  7. Mark Thorson says:

    carc studies? What’s that?
    I’ve seen some studies that seem to show losartan is doing something beyond its role as an ARB. My interest is primarily in Alzheimer’s disease, and this caught my attention:
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2806632/pdf/bmj.b5465.pdf
    Huge reduction in risk of incidence and progression of Alzheimer’s and dementia when taking an ARB vs. an ACE inhibitor, though candesartan had a stronger effect than losartan. I don’t think the effect of candesartan on GTPCH1 has been studied, but I’d guess it’s also an up-regulator like losartan. This study notes candesartan has better penetration of the BBB, which might explain its superior performance.
    Increasing BH4 in the brain certainly might have an impact on AD and dementia. In addition to being an essential cofactor for the nitric oxide synthases, it’s also an essential cofactor for tyrosine hydroxylase and tryptophan hydroxylase which perform the rate-limiting steps in the synthesis of the dopamine and serotonin families of neurotransmitters.
    I’m thinking that there might be an opportunity for a sartan-like molecule with enhanced BBB penetration and lacking the ARB functionality, so people with low blood pressure like me can take it to restore brain levels of BH4 to what they were in our youth.
    BH4 itself (a.k.a. sapropterin, Kuvan) has very poor penetration of the BBB. The BH4 precursor sepiapterin has good penetration and is effective for raising brain levels of BH4, so that’s another anti-aging drug candidate. Unfortunately, it has very poor solubility in water. Maybe it could be made into a prodrug form with good solubility, like a sepiapterin glycoside or something.

  8. DN says:

    This is a good approach. Old folks tend to develop global degeneration, not local wear and tear. That implies that soluble hormones are delivering the “fall apart” message everywhere.

    People interested in nitric oxide approaches should look at amlodipine, which seems to dissociate endothelial nitric oxide synthase from its storage complex (in addition to lowering blood pressure by blocking calcium channels).

  9. Anonymous says:

    I think the pension and debt crisis is more of a disease that needs curing than aging. Old people should die to make way for the young and productive, that’s how it’s supppsed to work, and the only way any species or society can be sustainable. “Curing” aging would end up killing society as a whole.

  10. Anonymous says:

    P.S. As a general rule, if old people can still work, or look after somebody else’s kids while they work, then that’s fine and they should live. But if they have to be looked after by somebody else who could be out working for society, then they should be left to die.
    Vote for me as President! 🙂

  11. Anonymous says:

    I wouldn’t call aging a disease per se, but rather a collection of a lot of problems with varying degrees of interdependence.
    I do think that we should definitely think of it as something that can be overcome. I think effective treatments for different aspects of it will come at different times, but I see no reason why it’s an inherently insurmountable problem. At the very least we should be able to greatly improve the state of affairs even if we can’t get rid of death entirely.

  12. Anonymous says:

    As we age our metabolism changes. Many components of the mTOR network are modified by O-GlcNAc, such as PI3K/Akt/cMyc/RPS6, which regulates their activity:
    FEBS Lett. 2006 May 29; 580(13): 3051–3058.
    Cancer Res. 2013 Aug 15;73(16):5277-87
    Mol Biol Cell. 2010 Jun 15; 21(12): 1922–1936.
    O-glcnac also cycles on proteins at promoter sites of genes that are heavily involved in regulating immunity, stress, and longevity:
    Proc Natl Acad Sci U S A. 2010 Apr 20; 107(16): 7413–7418.
    Can aging be treated as a disease? Possibly…..if we treat it as a metabolic disorder. A change in carbohydrate metabolism can go a long way in rewriting how your cells work. Maybe this is why a drug like Metform, which alters glucose metabolism, is a prime candidate for attacking aging. Is it altering your patterns of O-GlcNAc?

  13. matt says:

    I think the problem is poorly formulated when you refer to “treating aging as a disease.” That formulation is framed for these over-optimistic, Kurzweil-singularity-spouting, modern versions of deSoto. They are going to fool themselves, because they want a particular answer from their tests and the excitement of chasing historic life extension outweighs the cost of fooling themselves.
    It’s untestable and a protean goal that can be back-applied to any treatment that improves life expectancy in a condition we associate with older people.
    Phrased differently, we’ve seen comments come in when the topic is CFS or ALS or other diseases, where the pharma view is that someone is scamming them, and the sufferers of that disease flood the comments with something like “how dare you crush the tiny little hope this affords?” Well, _we_ are all infected with the incurably fatal disease of life, and we all must exercise extra caution against the Dr. Ozians telling us exactly what we want to hear and trying to hit exactly the right notes of caution to unlock our wallets.
    I agree with you that investigating things is reasonable, we might find useful things to tweak after screwing things up a zillion times, but following Feynman’s dictum to avoid fooling ourselves is going to be very hard, because there is no unbiased researcher.
    However, formulating it as “significant positive effect on overall survival rate of this intervention, beyond just the conditions it was previously approved for” is a good one, IMO. Especially for the FDA. That’s a quantifiable benefit they can compare to the downsides, and there are always downsides, and approve. They’ve always been willing to forego a thorough understanding of the mechanism as long as the effect was reasonably well demonstrated.
    Whether it’s “treating aging” or just curing/preventing a few more cases of diseases we know about, it’s a quantifiable benefit and we can operate on that basis.
    If we do ever successfully treat aging, it will be something we recognize decades after the fact, IMO.

  14. DrSnowboard says:

    The extra years you’ll gain with the body of an 82-year old will mean you have no life as a 28 year old trying to work out how to afford your planned extended years…. Quality not quantity anyone?

  15. Vanzetti says:

    @9:
    >>I think the pension and debt crisis is more of a disease that needs curing than aging. Old people should die to make way for the young and productive, that’s how it’s supppsed to work, and the only way any species or society can be sustainable. “Curing” aging would end up killing society as a whole.
    I don’t think you quite understand. Curing aging, actually curing aging, means there are no more old people. Everyone is young, some people just been young longer than other.

  16. Anonymous says:

    @15: “I don’t think you quite understand. Curing aging, actually curing aging, means there are no more old people. Everyone is young, some people just been young longer than other.”
    Yes, I understand. But unless you prevent *all* the ailments of aging at once, then all you’re doing is increasing the number of people with the ailments you don’t tackle.
    And in any case, I think the idea of fighting against nature like this is revolting. People should just age and die gracefully to make way for new beings and new ideas. It’s bad enough trying to convince someone with 20 years of experience that they don’t know everything, never mind someone with 100 years or more experience.

  17. pharmacologyrules says:

    @7 MT carc studies are the 2 year carcinogenicity studies

  18. Proteus says:

    “Plans call for the trial to enrol 3,000 people aged 70–80 years at roughly 15 centres around the United States. The trial will take 5–7 years and cost US$50 million, Barzilai estimates, although it does not yet have funding.”
    Normally I’d make a comment about how no one in their right mind will fund a 6 year $50mm study with Metformin as the potential product, but the capital markets right now might just buy in to it…

  19. Vanzetti says:

    @16:
    >Yes, I understand. But unless you prevent *all* the ailments of aging at once, then all you’re doing is increasing the number of people with the ailments you don’t tackle.
    That’s what medicine is doing at the moment anyway, without deliberately fighting aging as a concept. The better we are at curing cancer, the more old people will survive cancer, and then will develop other ailments at later age. The same is true for other kinds of diseases.
    >And in any case, I think the idea of fighting against nature like this is revolting.
    The entire history of the human race is one big fight against nature. Look around you – nothing around you is natural. Clothes you wear, car you drive, the computer you use to talk to me, the food you eat – all are fruits of technology.
    >People should just age and die gracefully to make way for new beings and new ideas.
    Are you against antibiotics as well? Germs, after all, are perfectly natural? Should we just let people gracefully die of pneumonia, “to make way for new ideas”?

  20. Anonymous says:

    @19: I actually agree with everything you say … but I also think we’re fighting a losing battle now, which has finally caught up with us.
    Just look at how total debt (public and private) is now at 350% of GDP in the developed world, and still growing faster and faster, while GDP growth is getting slower and slower.

  21. Anonymous says:

    Reminds me of this: http://linkd.in/1N94886

  22. Another Kevin says:

    “P.S. As a general rule, if old people can still work, or look after somebody else’s kids while they work, then that’s fine and they should live. But if they have to be looked after by somebody else who could be out working for society, then they should be left to die.”
    Wow.
    I’m surprised you don’t go the logical next step and assert that the old people who are working are taking the livelihood away from younger people and should be forced into retirement and THEN left to die.
    After all, if you’re the same “Anonymous” who wrote:
    “It’s bad enough trying to convince someone with 20 years of experience that they don’t know everything, never mind someone with 100 years or more experience.”
    the idea has to be lurking in the back of your mind.
    Logan’s Run was supposed to be a novel, not an instruction manual!

  23. David Cockburn says:

    @16. “It’s bad enough trying to convince someone with 20 years of experience that they don’t know everything, never mind someone with 100 years or more experience.”
    It’s also difficult to convince someone just out of university that they don’t know everything. Arrogant b***ds.

  24. Vanzetti says:

    @20
    >but I also think we’re fighting a losing battle now, which has finally caught up with us.
    If it’s a losing battle, then we should bloody well go down fighting!

  25. steve says:

    I think the discussion is a bit confused. Aging is a complicated phenomenon. First there is cellular aging, which involves telomere degradation, accumulation of chromosome alterations, etc. Then there is tissue aging that involves cross-linking of collagen, advanced glycosylation end products (AGE’s formed by the Amadori reaction and rearrangements) and other forms of tissue stiffening. Then there are organismal changes that include an increased inflammatory state and metabolic changes due to compensatory changes in different organs. Any one of these can lead to pathological sequelae such as increased rate of cancer, myocardial infarction and heart failure, etc. I think the idea of looking at medicines that can prevent some of these phenomena over time while preventing their pathological sequelae may be less emotive than just saying that you’re going to affect “aging”.

  26. Anonymous says:

    @24: Fight what? Or fight whom?

  27. Anonymous says:

    @25: So what’s the difference between all forms of medicine and fighting various aspects of aging? I mean fundamentally, without picking over arbitrary technical definitions? Because even infectious diseases correlate with aging, since the longer you live the more time you have to encounter them…

  28. Crocodile Chuck says:

    ‘Death is the most important invention in history’ Steve Jobs [Stanford Commencement speech 2005]

  29. sgcox says:

    If ageing is a slow degenerative disease then puberty is surely an acute inflammation. Shall we design drugs for it too ?

  30. steve says:

    @25, that’s exactly my point – let’s discuss agents that attack specific processes involved in specific pathologies without gumming up the works by calling them anti-aging drugs.

  31. Anonymous says:

    I think complete mandatory birth control is our best bet.

  32. Slicer says:

    @28: Steve Jobs killed himself with his own company mascot. Turns out that a diet in which fructose is the only source of your calories is a really bad idea.
    There’s almost always a death cultist every time this topic gets brought up, like clockwork. Someone, probably someone very young who doesn’t understand what it is to slowly degenerate, always says something stupid about old people needing to make way, everyone has to die, yadda yadda, every time.
    Go away, @16. Get yourself killed, not the rest of us.
    The rest of you: Look for ways to reverse the damage that defines aging (stem cell depletion, senescent cell accumulation, glucosepane stiffening the arteries, every biological change that defines an old person as not young), and if you’re at all successful, you’ll find treatments that ameliorate or outright cure potentially fatal conditions that can be easily identified by the FDA.

  33. Anonymous says:

    Lane: There certainly isn’t universal agreement on the AMPK is harmful idea. Plenty of people think it may be beneficial. It is one of the few targets that is known to up-regulate during caloric restriction, for example.

  34. Mark Thorson says:

    There’s some evidence implicating AMPK as the link between amyloid beta and tau hyperphosphorylation in Alzheimer’s Disease.
    http://www.columbia.edu/~fp2304/Polleux_lab_publications_files/Mairet-Coello_Neuron2013.pdf
    These are relatively late events in AD, so I don’t think they cause AD, but they may play an important role in progression of the disease. In particular, they may play a key role in the progression from mild AD to moderate/severe AD.

  35. Anonymous says:

    @33: Certainly I don’t think evolution works by selecting for harmful functions.

  36. Lane Simonian says:

    #33 It is probably mainly a timing issue where the activation of the AMPK has beneficial effects in the absence of oxidative stress.
    Mark, thank you for the link to this important study. Another problem created by AMPK under conditions of oxidative stress is due to its activation of p38 MAPK. Your observation about where the activation of this kinase fits into the progression of Alzheimer’s disease is likely an accurate one.

  37. Mark Thorson says:

    Lane, you are a crank.

  38. Lane Simonian says:

    Mark, maybe we are both cranks, since I am largely agreeing with you.

  39. Orv says:

    @9: I don’t think it would necessarily kill society, but it *would* force a radical rethink of the way our economy works. We’re going to have to do that anyway, though, even if we don’t lengthen lifespans As more and more jobs are automated we simply don’t have enough jobs for everyone to have one, but we’re heavily invested in the idea that someone has to work a job to deserve to live.
    I tend to think the solution is to rethink the way the economy works, not let people die so we can continue business like usual. But that’s really not medicine’s problem to solve, IMHO.

  40. Anonymous says:

    @39: I like you’re thinking. Either way, we need something radical, because we won’t last long the way we’re going.

  41. gippgig says:

    #39: This is the agriculture story all over again. Just as the development of agriculture enabled a fraction of the population to produce all the food that was needed, technology is enabling a fraction of the population to produce all the wealth that is needed. I think the solution is the widespread ownership of shares of businesses – machines do the work, businesses make profits, & people live off the dividends.

  42. Alex Larsen says:

    I would be interested to know what you think of Aubery de Grey’s work into anti-aging therapies.

  43. Cesare Renzi says:

    @9 and of course @16
    Every time there is one, a fox talking about grapes. I am amazed by the persistance of this kind of mentality, the “it’s the circle of life” thinking of people who “accept gracefully” aging because “Nature knows best”.
    Nature is NOT an intelligent agent, and you cannot possibly go against Nature because you are a part of it – a skyscraper is as much part of your precious “Nature” as is a termite mound.
    What the hell people, just find me an optuagenarian who’d rather stay as he or she is rather than shave off 40 years or so: we all want to live, in passable conditions.
    I’m not saying it will be easy, nor I ascribe to the overly optimistic thinking of, to mention one, de Grey, but ruling off this line of research as infeasible is akin to those parsons lamenting the first steam locomotives as the work of the devil.
    P.S.: I’m sorry for derailing this discussion into inane rantings but I simply cannot stand the aforementioned stance regarding this topic.

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