Targeting Aging is the Way to Treat Diseases of Aging

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/

Comments

This will change when the first generation of sens-like therapies are out. It will become clear that removing damage is far more efficient that the so-called treatments that will only compress morbidity just a little. I would say the 2030s will be the turning point, when we get a dozen of solid senolytics therapies used widely in the world.

Posted by: Jonathan Weaver at October 26th, 2020 7:02 AM

This will all change when the first visibly obvious rejuvenation therapies are successful in humans, be they direct repair, partial cellular reprogamming, or whatever. If it works and people can see it worked they will get on board. Seeing is believing.

Posted by: Steve Hill at October 26th, 2020 7:58 AM

When the first therapy works to rejuvenate the looks it will be used by the celebrities even if it carries great risks since being at least apparently youthful can extend ones career and bring significant monetary and status benefits. The same logic can be applied to the professional sports but there it will be less about the looks but rather about keeping the top shape and performance. The chance to stay in the top league will be used and abused, sometimes with horrible outcomes. But the therapies well be unstoppable in the large scheme of things.

So far we no indication that this is happening. I would expect a football creme of senolytics or rapamycin to slow the skin aging visibly. I was expecting a couple of days ago that by now we're woke have some human data that is convincing enough to set up some private clinics that are not shy to use the unproven rejuv practices.

Posted by: Cuberat at October 26th, 2020 8:44 AM

If atherosclerosis is a "disease of aging" and some lifestyle choices can reverse atherosclerosis, does this mean that lifestyle choices can reverse aging?

Why do some people in their thirties have atherosclerosis and many in their seventies do not?

Posted by: Lee at October 27th, 2020 6:31 AM

@Lee
It is a disease associated with aging but not aging itself. The disease is the final pathology of a long chain of events. If you can reverse the root causes probably you can reverse the disease too

Posted by: Cuberat at October 27th, 2020 8:21 PM

Hi Lee! Just a 2 cents.

Yes, absolutely, lifestyle choices can definitely help out on the disease itself; but on the aging matter, that's more nuanced...you can slow it down a little bit, let's say...Aging is many things happening all in tandem; from epigenetic clock demethylation/Global DNA demethylation/ hypomethylation (to hypermethylation of CpG DNA pockects), from oxidative lesions (8-oxodG) (and then, litterally, Deletions of 'chunks' of nucleotides) - building up in the mitochondrial DNA, to chromosome becoming loose (DNA uncoiling)/losing histones, accumulating mutations in mitos and nucleus, to accumulation of junk residues/oxidized residues/dead weights in many parts, to damage marks on telomeres (y-H2aX foci), to overproduction of ROS (reactive oxygen species/'free radicals') at mitos, all this compounds to make the epigenetic clock advance ('age you'/'age the signature 'identity' of you' inside - in other words, your body is 'officially 'tagged' 'as Older'...this tagging, creates a different signature depending on how many tabs/tags you accumulate over time, and thus closer to natural death).

Lifestyle choices changes can have not unsubstantial impact on lifespan, thus sizeable; just the fact of starting to do CR (Calorie Restriction)/fasting here and there as a tradition...all this will activate several 'conserved mechanisms/strategies'....which yield better health...and do increase longevity, a bit. But themselves alone are not enough to make you live much beyond the theoretical 120-130 human limit (well..it's not theoretical...it's pretty much 100% assured that no human lives much beyond 130...because we can see it inside the cells; way ahead; telomeres tells us that; people thathave slower telomere shortening rate could very much live Over 120...heck they could live centuries with an s'; but so far nearly every healthiest human alive 'shortens at same roughyl same speed'...no matter how much CR, jogging, eating veggies...or even taken tons of supplements...supplements and CR slow down shortening rate...but not stop it, far from it). The Biggest contributor to aging, by far, is happening each second that you breathe air; Aging is caused by the air you breathe- which is needed to create cell energy; but this process (catabolism) is what causes 'faultyness'/it's not error-free and Oxidation is an ever present phenomenon..rusting of stuff by exposure to OXygen Racidant Oxydating (ROS) macro-molecules in your body; damaging them over time, over long-term exposure to these ROS free radicals. Mitochondria are the largest producers of them...they go on to create DSBs (double strand breaks in DNA), and SSBs (single strand breaks)...this is fragmentation/fracturing of the DNA...means acceleration of aging by destroying DNA content - due to Oxygen exposure/ oxydation phenomenon. On top of that, metabolism is the 2nd largest thing controling your lifespan - whether 'lifestyle choices' or not....metabolism makes lots of 'byproducts/end-products' will are you know..like exhaling CO2 (carbon dioxide), this is part of the metabolism...we are fast metabolism and normally we would live 25 years or so..but we countered that (or let's say evolution did that not us), with radical quenching/consumption (antioxidant systems that are able to 'catch' radicals...and render them inert..thus, quench/consume them; so that don't go on to damage every macro-molecule..or produce More byproducts and that They go on and cause havoc in a downward spiral 'cascade'/chain 'downstream' of the whole processus).

Some people in their thirties (like I was a few months ago...now I'm 40) can get atherosclerosis; (like me, for example...I got it). But I found ways to survive it, I Had to or I would be dead.
Why would then people Younger get it...then older....because it is complex, familial genetic inheritance is an important element why you might get it earlier (Than later); a young person, it was shown in studies, his/her cells are primed for long-lifespan (because younger), but a young person's cells can also die Quicker/if struck/stricken...than an older person...that is because an older person's cells developp strategies, developp acclimatization to 'pain'/injury...it's part of 'getting old'...so the saying is 'get used to it'..in old people, it applies, you have to Survive (the pain/injury) to live to Be Old...you won'T reach it...you have to be healthy of course; but if can't survive 'injury/insult' in young age...won't reach old age. But, as said, younger cells can 'spontaneously' 'exit cell cycling' too....even more if 'overstressed'...because they are not as 'adapted' as old cells to insult/oxidative burderning...old cells have a long-standing..of benig there/around...they reached that milestone 'of still being there/around'...so this faced many challenges; they had to survive them and keep 'overall' levels Low all the time; but they still could face 'challenges' 'Spikes'...young cells are less adapted to these 'improptu spikes/challenges'/they are more 'susceptible' to them (older cells became less susceptible by adaptability/cell memory)...the young cells can simply decide: ''premature exit of cycling''; which means premature 'spontaneous senescence'..in young.

Thus, you can be frail in old age...but you 'toughed it'...in young age...you can be frail too (I was...I nearly died of it, by atherosclerosis; I went down to 100lbs...I measure 5'10...100lbs or less can be deadly for someone this tall; it is meager/very thin and can suffer frailty), I was Not Obese Ever in my life (always 125-150lbs never more in adult age)...I still nearly died of atherosclerosis..doesn't matter fat or not...if you have atherial weakening/artery 'clogging' (as it was my case)...then you can die thin of it...Being Obese Only Accelerates the whole thing...but don't go thinking because you switch on veggies or jog or fast all is dandy...no. Lifestyle changes are Long, take a long time to repair/heal..it took me 5 years and still reeling from this...I know it will only get harder..because I suffered 'epigenetic aging' in my vasculature due to this d*mn diseaes....so I could end up dead of it in the next 50 years if I do nothing...to avert it as best as I can; becaus now it is a disposition/condition/an actual 'epigenetic insult' about me and have to deal with that. Same thing with people that are obese and become thin..it's because become thin..all solved; you were obese and this creatd epigenetic landscape problems/marks...they do not leave...thus you can die faster..than people Who never were obese in the first place. Everything that happens to your body leaves a mark, especially dire events (like a disease, like atherosclerosis; a silent killer). Also, one more thing and to end, young people are not immune to any diseases 'of old' basically...you can get it Much Much quicker in your life than you ever thought...senescence happens at all ages. Old people were able to 'slow it/minimize it' enough to live this long (thus, were lucky...it's not just 'they changed lifestyle'...it's a combination of things, including their very genetic makeup) You may be young and it's not possible for you/your body/your genetic/your inherited makeup/gene defects born with, hence you can ahve senescence aplenty, young too. Plus, atherosclerosis is scary...because you feel healthy...and one day silentyl, it comes...just like 'stage-4 cancer'..same thing...you never knew...until one day - Pain...you go for a scan...you are told 'you have stage-4 cancer'....that's atherosclerosis, same silent kiler, as like cancer. One day, you feel pain in the chest like someone stabbing you repeatedly there, or like 'twisting/snapping a twig'....your arteries are Extremely fragile and Extremely Sensitive...you will feel pain like never felt in your life/deathly pain...so deadly. you can pass out and Wish to die (to stop the pain).Torture is a joke compared to that and when people say I feel pain. No, you will feel (real/deadly) pain, when someone tears your vasculature...you can die on the spot. Now, that I lived it (and nearly died of it...but survived it), I can say I never want to feel it again, once you feel it, you prefer dying because it is too painful; it amputates you from inside (like imagine losing All your limbs...like that only 1000time worse because though being crippled and alive is bad life quality, you are still alive; the other choice, is dying) and is a Very Scary feeling; like an 'impending doom'.. when this feeling comes, you know you will die (very soon, possibly in the next 30 seconds, that kind of feeling). I felt it, and I saw my 'life flash before my eyes in a fraction of a second' (your brain does that...it does a 'recollection of your past - in a 'giant 1sec ultra-fast dream'...while awaken. It is teling you : 'I know it is the end in a fraction of a second coming...but I want to show you Your Life/The People In Your Life/The Moments of Your Life That Mattered....one last time in résumé.. before closing'.

Just a 2 cents.

Posted by: CANanonymity at October 28th, 2020 9:14 AM

Hi, CANanonymity! Just want to say that I love your posts (however long they may be), they're always very interesting and informative for someone like me, who knows nothing of biology and biochemistry. I am, however, very interested in these matters, as I'm no spring chicken anymore (approaching 60) and, as I run out of time, I like to think that some day something will be done about this dreadful condition we all go through. Small consolation I know, but it's all we have for now. I hope you are well now and wish you a very long, happy life, free of pain.

Posted by: mcmp at October 28th, 2020 9:54 PM

Hi mcmp! Thank you very much for that/for thoughftul wellmeaning/kind thoughts. I agree 100% with you, the faster we can fix aging the better we all will be. I am better now but still hurting because it was like a devastation, and rarely leaves you 'scratchless if you do 'go through it' and continue living/surviving your once near-demise (when so many people perish of my disease (older, being younger it sort of protected a little bit but even young people can succomb because not 'used to challenges like that'); I know I am very lucky and count my blessings/grateful to life (for, I could be gone due to it); but, though it's a mix of things; luck but also resilience/the will to live/changing things/lifestyle change etc..., or else I could have given up and let the disease and pain take me; it's why I am so anal retentive/annoying about people seeing the seriousness of 'having just 1 life' and doing all you can to preserve it...it's precious like that and can be gone like that too (I don't think in months/days/hours/seconds..I think in 'breaths'/heart beats), if you let it be/let a disease win over you/your life; thus, your will/to live, resilience, hardiness, sky high pain threshold and being grateful, to (still) have a life). We all face challenges/battles in life, some more than others...but we have to compose well with them, biological/life demands it; life cannot work (for very long) if we are so unhealthy for so long and developp whatever diseases of old, whether young or old; still must survive your odds...it's like being 'dealt a hand' (cards poker) in card games..you have to make do with what comes...
..'comes what may. As and more elder yourself, I learn a lot from elders and they have so much to teach us youngin folks. High Respect, bless you.

Wishing you, too a very long health/long life, the longest can possibly get!!
And wishing that to all too.

Posted by: CANanonymity at October 29th, 2020 12:25 PM

CANanonymity, thanks for your kind words. You're right, life is an endless, fruitless struggle and no one comes out of it alive. It is what it is... God bless you too.

Posted by: mcmp at October 30th, 2020 5:52 PM

Hi CANanonymity-I have extreme dyslipidemia so my doctor would like me to use statins. I'm on the fence with regards to statins.

Do you have any non-medical interventions that help substantially to improve lipid levels?

Posted by: Ambrosia at December 5th, 2020 8:43 AM

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