#321

Hello Dr. Frazer, I understand that many patients on GLP-1agonists develop constipation, especially with a predisposing tendency to the problem. Patients who take SGLT2 inhibitors are prone to worsening of urinary frequency and UTIs. Both problems are common in elderly population. How do you deal with these problems?
I even developed constipation on Pendulum GLP-1 Probiotic.
Thank you!

#322

Good question - this is a multipronged approach and everything is dose dependent.

So for GLP-1’s, first, with a primary plant based whole food diet (feel free to add a little fish, fermented dairy and if desired other little bits of meat) will be a high fiber diet with lots of bulk. Individuals pursuing this get multiple health benefits, but also tend to tolerate GLP-1’s. I recall possible ~2% of my patients having an issue with this - and those individuals have gone down on dose, or switched GLP and have tolerated it to the benefit of their metabolic health.

The SGLT2’s tend to have a long half life - but still, taking them in the AM is smart. I’ve not noted a big issue with urinary frequency for most, but the UTI issue is a real one - and some individuals who get them repetitively, just shouldn’t have these agents. Naturally, the moment you think you have a UTI, cease this medicine until it is treated and better as the bacteria have a feast on all the glucose coming into the urine. I’ve got a handful of people with this issue, and the SGLT2-i’s just aren’t a match for them.

I don’t think Pendulum is comparable to an injectable GLP-1 … I appreciate their view that it might have some action in this space - I’ve not found it to be clinically meaningful.

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#323

Have you seen this?

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#324

also:

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#325

Sadly, the mouse model has proven problematic with AD. I’d like to see human data of some type - the problem is so many people with malignancy have neurologic damage as part of their treatment and as such they aren’t often a good group to study for neurological decline.

I don’t see a situation based on this that I’d do more than watch this space. Risk / Benefit would favor doing the things we know help in the prodrome. Once someone has significant disease, I’m not convinced yet of any intervention that helps - which is why doing sensible stuff 20 years before predicted onset of disease (if you’re going to get it) is pretty sensible.

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#326

I think fixing AD any other way than fixing “aging” will be really hard.

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#327

Unless it’s early onset AD. If AD is a distinct disease and not intrinsic to the aging process, then there is hope of addressing it apart from any aging intervention. Aging may increase AD risk, but there is a distict AD pathology that can start very early in early onset AD (30’s and even earlier) that has little to do with aging.

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#328

Interesting assessment. I think it is part of aging to a degree - and I suspect we are probably in agreement but just looking at aging differently.
For example with death every 8 years of life through adult life risk of death doubles.
If we look at the curve of age vs. AD - age is a critical factor. If one has homozygous ApoE4 if you are 58 years old - you have almost zero risk of having AD - but by the time you are 72 years old - you have a 50%.
If we can effectively delay aging … do we shift that curve to the right by however many years, does this shift the rate of AD by age?
I suspect so.

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#329

I see it differently. I see the AD pathology along the same lines as atherosclerosis. Atherosclerosis (to simplify) is the process of plaque accumulation. Yes, with more time/years - more plaque accumulates, but the plaque accumulation is not driven by the age process per se. “If we look at the curve of age vs [Atherosclerosis] - age is a critical factor” - well, yes, but only insofar as aging necessarily gives more time for the pathology to accumulate damage. But the time factor is incidental, the underlying pathology has nothing to do with aging - because if you intensify the pathology, you don’t intensify it by accelerating aging, you intensify it by increasing plaque deposition, the example being familial hypercholesterolemia. With FHC, you can have children as young as 6 years old or even 3 years old accumulate enough atherosclerosis to have heart attacks - we don’t see the aceleration of the pathology by premature aging, the 6 year old doesn’t have accelerated aging, the child has accelerated plaque deposition. To take an extreme example: gangrene. Untreated gangrene will spread and eventually kill you. That is a factor of time - yes, with more time untreated gangrene kills you, but that’s not due to the aging process. It has to do with the pathology.

This is why I mentioned early onset AD as showing that this is a pathology that is not intrinsic to the aging process. You have an underlying pathology one of the manifestations of which is the spread of tau protein. If that happens when you are young - young onset AD - the greater spread of tau in younger people manifesting AD is not due to the younger person experiencing accelerated aging, but accelerated pathology, same as in the atherosclerosis example - you could call FHC “early onset atherosclerosis”.

Earlier Alzheimer’s disease onset is associated with tau pathology in brain hub regions and facilitated tau spreading

https://www.nature.com/articles/s41467-022-32592-7

It’s not the age that’s the problem. It’s the pathology that’s the problem. You can have old people without the pathology, and they will not have AD. You can have young people with AD, and it’s not because they became prematurely old.

Therefore, trying to delay aging will not solve the problem of the pathologies: atherosclerosis, AD, gangrene. If you slow aging, so what - you are still depositing plaque in the arteries at the exact same rate. If you slow aging, so what - you are still spreading tau proteins at the same rate. If you slow aging, so what, the gangrene is still spreading at exactly the same rate.

These are distinct processes. Aging might make you more susceptible to certain pathologies, but the predisposition to these pathologies must already be present. The pathology as a distinct process must be addressed on its own terms, and trying to do it through delaying aging is not going to work. AD is a disease. Address the disease directly.

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#330

Yes - I’m not talking about the early onset which is less than 10%, I’m talking about the aged onset 90% of AD which is absolutely linked to age - and presumable aging.

Atherosclerosis is absolutely related to age - but is is due to aging? We always look at this as intensity of vascular insults x time. Does slowing aging result in it requiring more time to get the same level of disease?

My suggestion is slowing aging is effectively slowing the rate/impact of insults on our system, be it brain or vascular system and it would make sense (and we see this in individuals who do things to have a good lifestyle - they get the same diseases, but they shift it out 10 years from what would be average).

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#331

Right, but I don’t agree :sweat_smile:. From my reading of the literature, atherosclerosis is not driven by age per se, age simply makes you more vulnerable to the underlying pathology. If you don’t have the pathology, then aging will not magically make it appear - that is why you can have old people with no atherosclerosis. But if you have the disease susceptibility, then older blood vessels will indeed start manifesting the pathology, because they have less resilience and lose integrity - now plaque can accumulate more, but if there is no plaque present, you won’t accumulate it. It’s about plaque, the pathology, not the age.

It is a distinct disease apart from aging. When you look to ameliorate the disease, you address it directly. And one way is to address the pathology of plaque accumulation is by for example a statin. A statin will slow or stop the disease directly regardless of age. A statin addresses the pathology, it doesn’t affect your age and it doesn’t slow down your aging rate. It’s not connected to age, but to the pathology. The same way an antibiotic addresses the gangrene pathology and not aging.

From my reading, AD is the same way. It’s a pathology and not a part of normal aging. It accumulates damage with time just as atherosclerosis does and gangrene does. If you don’t have the pathology, you will not get atherosclerosis or AD or gangrene with age as it is not due to age, and in treating them you don’t address aging by using a statin or antibiotic. We need an equivalent of statin or a collection of other therapies to address AD, and it won’t be by slowing aging.

And the point of mentioning early onset AD is that it’s the exact same disease, just more severe, just as FHC is also atherosclerosis, just more severe. If you address FHC directly it will stop or slow the disease not the aging. If we address the disease, the pathology of AD, we will also stop it and it will also not slow aging.

Anyhow, that’s my view, based on my reading of the literature. I’m not being argumentative, I’m just passionate about AD, because I’ve seen the effects (in for example my maternal grandmother), and I want to understand and do all I can to help. So I’m just exchanging views.

All dementias are pathologies with distinct presentations and etiology. PD can lead to LB dementia. That’s pathology and not part of aging, just as FTD is, and AD is. We don’t all gradually get AD, LBD, FTD as we age, only some people, because these are all diseases and not part of the aging process. Slowing aging will not slow AD, LBD, FTD, VD, AS. As Matt Kaeberlein said, you can both slow down aging and die prematurely due to a disease process, because there are diseases not dependent on aging. I don’t need to slow aging to stop atherosclerosis with a statin, and we can stop AD without slowing aging too, we just need to find a statin equivalent therapy to address AD. I think it can be done, and I’m optimistic that we will have some answers within the next five years from what I understand looking at the work being done as we speak. We won’t slow aging, but we will stop AD!

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#332

I think like many aging disease it depends which one gets you first (or which few). It obviously can be exacerbated by environment, but I think the failure to produce new endothelial cells is part of the aging process. I did a quick O3 question which I link below with the usual warning about hallucinations.

#333

How so? How is the failure to produce endothelial cells part of the aging process?

Instead, it is not the aging process per se, but the pathology of atherosclerosis, the atherosclerosis is the disease. That is borne out by your very link:

“Atherosclerosis creates a hostile biochemical and biomechanical environment that (1) suppresses the supply of endothelial progenitor cells (EPCs) and (2) impairs their maturation into healthy endothelial cells. That failed renewal leaves denuded or dysfunctional endothelium unrepaired, which accelerates plaque growth and instability —a vicious cycle.”

It’s atherosclerosis that creates a hostile biochemical/biomechanical environment, not aging. Atherosclerosis is a disease. The aging process by itself does not generate atherosclerosis.

From your link:

“Fewer and weaker EPCs: People with cardiovascular risk factors and atherosclerosis have reduced numbers and function of circulating EPCs, which predict faster disease progression and poorer vascular repair.”

Again, cardiovascular risk factors and atherosclerosis. Disease, not the natural aging process. If you have underlying disease factors, yes, with time they can manifest. But again, that’s disease - absent the disease and underlying risk factors, you will not manifest those simply in the course of time (natural aging).

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#334

O3: Yes. Across multiple studies, the number of circulating endothelial progenitor cells (EPCs) declines with advancing age, and their migratory/repair function also wanes. This has been shown in population cohorts and clinical samples using common EPC phenotypes (e.g., CD34⁺/KDR⁺ with or without CD133). The age effect is seen even after accounting for cardiovascular risk factors, though these risks further depress EPCs. (New England Journal of Medicine, JACC, JACC, PMC, PMC)

Notes:

  • Definitions vary, which can change absolute counts, but the age-related downward trend is consistent. (PMC)
  • Exercise training can partially and transiently increase circulating EPCs in older adults. (PMC, SpringerLink)

If you’re working with a specific EPC assay (flow cytometry markers vs. CFU assays), I can tailor the evidence to that method.

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#335

Yes, atherosclerosis is multifactorial. And blood vessel integrity declines with age, lumen is compromised, endothelium etc, but that only matters if you have factors that result in atherosclerosis. If there is no plaque being generated due to a disease process, the age compromised vessels don’t result in atherosclerosis. If you do have disease factors, then yes, aging can definitely exacerbate the disease - that is common for all diseases, age is an exacerbating factor if disease is present, but in and of itself does not generate the actual disease. You still need the disease to occur, the pathology, for aging to make worse. So it gets back to the etiology of the problem - it’s not age, it’s the disease (here: atherosclerosis).

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#336

I appreciate the alternative perspective—so let’s take a look at the data. If we graph the most common causes of death and disability by age—coronary artery disease, Alzheimer’s, stroke, chronic lung disease, Parkinson’s, cancer, sarcopenia, and infections (which are bimodal: high in infancy and then rise steadily with age)—a clear pattern emerges.

The trend is remarkably consistent: with increasing age comes a sharp rise in risk for nearly every major disease.

Yes, correlation isn’t causation. But when nearly every leading cause of death and disability follows the same age-related trajectory, the association is hard to ignore.

Now consider the Blue Zones. I’d argue these populations have effectively slowed their rate of aging. They still die of the same diseases as everyone else—just later. The whole curve shifts to the right by about a decade.

So here’s the practical takeaway: if your lifestyle or interventions are expected to delay your biological aging, it stands to reason that the onset of age-related diseases will be delayed as well.

Whether you frame it as “delayed aging leads to delayed disease” or the reverse, the end result is the same—each of these diseases appears later in life. And while the pathologies differ, the pattern of delayed onset is consistent.

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#337

Well, there is the old argument, partially semantic, whether aging is a disease (or collection of diseases) or a natural process that’s the result of how the body is designed (designed in the sense of construction by evolution). You seem to favor the “aging is a disease” model. I favor the “aging is the result of evolutionary design”.

We all agree that bodies fail and die as a result of aging. They can also fail and die as a result of disease - I think(?) we agree on that too. But a more subtle point is that in my understanding bodies must age and die without disease being the driver of that failure and death - this is where I believe we differ. Correct me if I’m wrong in understanding your position.

Why do I think aging and death are not result of disease, but a direct consequence of design can be incapsulated in the concept of how telomeres work. Telomeres are a cap on the amount of time a cell can last controlled by number of divisions. When a telomere reaches critical length as a result of a number of divisions, the cell stops, senesces and dies. It does not need a disease to die. Disease does not drive the demise of the cell, the cell demise is designed into the very construction of the cell - this is aging (and eventual death). In other words, cells do not need disease to kill them, they die by design.

This can be extrapolated to the whole organism. As the body ages, its resilience drops, the ability to repair drops, recovery to homeostasis drops. These are natural processes which are the result of how the body is designed, not the result of any particular disease. When the body reaches the limits of its design, the stem cells have been depleted, there is no more recovery, failure occurs. The acute event can be whatever the organ or system fails irrecoverably first - heart, brain, kidneys whatnot, whatever system resources cannot bring to homeostasis.

Now, it is true, that while the system ages and resilience drops and the ability to repair drops, the instances of non-communicable (and communicable!) diseases increase, and various vulnerabilities (cardiovascular risk factors, excessive ApoB production, dysregulated glucose metabolism etc.) translate into much increased rates. That is why these diseases increase with age, not because age causes them, but because as a result of age related changes the body can no longer defend against them.

This is where an element of semantic argument enters. If you are sitting in a secure home and outside the home are bandits seeking to harm you, but a family member Mr. Aging systematically dismantles the defenses in the house [by design - that’s what aging is], then eventually bandits will be able to breach the walls and start assaulting you. Now the question becomes - has Mr. Aging [age process] killed you, or did the bandits [disease].

Now consider the Blue Zones. I’d argue these populations have effectively slowed their rate of aging. They still die of the same diseases as everyone else—just later. The whole curve shifts to the right by about a decade.

Again, we might be getting into semantics here, but no, I don’t think blue zone populations have slowed their rate of aging. I think they have simply come closer to the full biological potential of human body design.

So here’s the practical takeaway: if your lifestyle or interventions are expected to delay your biological aging, it stands to reason that the onset of age-related diseases will be delayed as well.

No, I don’t think lifestyle and such interventions are expected to delay biological aging, they are expected to prevent premature succumbing to pathologies due to weaker defenses, weaker defenses brought on by the insults of unhealthy lifestyle and environment.

I think the following thought experiment can clarify our positions. Let us assume two identical individuals “A” and “B” with exactly the same lifestyles. They have the same biological profile and exactly the same rate of aging and the same disease - here we can pick anything we want, let us assume it’s atherosclerosis, which will kill them both at 75. You will say that the atherosclerosis - or AD, or whatnot is a manifestation of the aging process that killed them. I say it is a disease that killed them - atherosclerosis, AD whatnot, prematurely.

If I now put A on an effective lipid lowering therapy starting in youth - say a statin - “A” will live to 85, so a decade longer than “B” who was not put on a statin. “A” lived a decade longer because I stopped the disease process, not because I slowed down A’s aging. I wish to have a “statin” for AD. That too, will not slow the aging, but it will cure the disease and allow A to reach the full biological potential of his design, which is 85 - I have not slowed down the aging. Now, maybe (and that’s a big “maybe”) rapamycin would actually slow aging, and now A would reach 95, but for real results you have to change the original design, in the same way in which two extremely similar animals - both small rodents - the mouse and the naked mole rat have a very different genetic design, so one lives around 3 years at best and the other over 30. You cannot do that with any current lifestyle or drug intervention. Optimal lifestyle on the mouse gets you to 3 years, add rapamycin or longevity drug X, maybe get to as much as 4 years, but only a change of design will get that mouse to 30+.

Here is why our perspectives have practical consequences. If you treat AD as a disease of aging, where you need to slow down the aging to delay the onset of AD, then you are asking for a moonshot - you are asking to slow down the rate of aging, which we have no tools to do at present other than two - count them, TWO - interventions in model animals (CR and possibly rapamycin). That’s it. We have no other way to provably slow biological aging in mammals at present. I think that slowing down aging in humans is a HUGE ask. And ultimately, by your own words, it merely delays AD. Now, my approach is to treat AD as a distinct disease, just as atherosclerosis is - and I want to cure it. I want to eliminate AD, not just delay it. We have done so successfully with atherosclerosis, where by getting to rock bottom ApoB we have essentially stopped the pathology - and not merely delayed it. I want to stop AD.

Therefore framing AD and such diseases as diseases distinct from the aging process (even if prevalence increases with age), allows us to search for a cure without having to hunt for Ponce de Leon type moonshots. I’d love to slow down aging, absolutely, but I would also like to cure diseases in the meantime, I don’t want to wait until we all live to 150, because a lot of people get AD and such at much, much earlier ages. We should work on both, but I expect faster results from treating AD as a disease.

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#338

I love the detail of your response and sadly I’m time poor right now in being able to respond with the depth of analysis you have provided.

The good news is regardless of whether your assessment is correct or my assessment is correct (and BTW my actions are very much in line with your approach as your approach is actionable and mine is theoretic).

If you’ve looked a my talk at Vitalist Bay on my approach to the longevity medicine consultation - I micromanage and optimize every item that has high evidence. You are correct that if I image (which I do) and properly assess for vascular disease and stabilize any existing and avoid any new disease, I can virtually eliminate that cause of death. There are strategies I employ for all the common causes of death.

Now if one is a traditional physician and go by treatment guidelines, and don’t objectively image then aging will seem to be a massive component - but if I manage by my approach, then aging isn’t a factor.

One of the things I’ve realized, is that it takes a lot of effort and education to optimize everything, which has resulted in me having to change the structure of my practice. In order to properly mitigate and monitor everything, one can’t do it with 4 hours of physician time in a year …

Anyway, I do appreciate and have read all of your logic and it is sound and regardless of the component of aging vs. disease … the actions taken on the clinical side are not hugely modified by which approach is correct. I believe the answer will be somewhere between the 2 assessments and there is obviously a component of traditional disease progression - but also aging. Also, all these folks in the Blue Zones don’t die of “old age” they have a traditional disease that kills them. Age however increases risk of almost every disease in regard to frequency/year.

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#339

Lithium orotate for the win!

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Predicting Alzheimers & Dementia (and minimizing risk)
#340

I think the consistency of what is published on this topic with Lithium and AD or MCI seems a promising and cheap therapy, that should have very little in the way of side effects for most individuals. I personally take 5 mg of Lithium Orotate twice daily and have for a few years now.
Thanks for bringing this paper to my attention. I’ll need to do a video on this.
@CronosTempi The dose I take is 5 mg of DoubleWood Brand Lithium Orotate twice daily. It’s a trivial dose - when I’m treating individuals with bipolar disease, our dosing is typically 600-1800 mg of Lithium Carbonate daily (split into 2-3 doses, and levels checked). So this 10 mg daily I take is a trivial dose comparatively and I see no reason to check the level of this given that it would take at least 600-900 mg/day for me to get a level that could risk toxicity.

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