Calcium channel blockers reduce aging rate (ARDD video)

[AlexKChen]

Sara Hägg at ARDD2024: Drug repurposing for Alzheimer's disease using triangulation of evidence

Anti epileptics are an example

Esp new generation like lerni

[adssx]

Thanks a lot, @AlexKChen, for sharing this; it’s a great presentation. Sara Hägg is very good.

Tl;dr:

In Longitudinal associations between use of antihypertensive, antidiabetic, and lipid-lowering medications and biological aging 2023, they found: “Overall, using antihypertensive drugs was associated with a decrease in one DNA-methylation age (PCGrimAge: beta = − 0.39, 95%CI = − 0.67 to − 0.12). When looking into drug subcategories, calcium channel blockers (CCBs) were associated with a decrease in several DNA-methylation ages (PCHorvathAge beta = − 1.28, 95%CI = − 2.34 to − 0.21; PCSkin&bloodAge beta = − 1.34, 95%CI = − 2.61 to − 0.07; PCPhenoAge beta = − 1.74, 95%CI = − 2.58 to − 0.89; PCGrimAge beta = − 0.57, 95%CI = − 0.96 to − 0.17) and in functional biological ages (functional age index beta = − 2.18, 95%CI = − 3.65 to − 0.71; frailty index beta = − 1.31, 95%CI = − 2.43 to − 0.18). However, the results within other drug subcategories were inconsistent.”

In an unpublished Mendelian randomization they confirmed the anti-aging potential of CCBs:

In Comparative effectiveness of glucagon-like peptide-1 agonists, dipeptidyl peptidase-4 inhibitors, and sulfonylureas on the risk of dementia in older individuals with type 2 diabetes in Sweden: an emulated trial study 2024, they found that “GLP-1 agonist initiation was associated with a reduced risk of dementia compared to sulfonylureas (hazard ratio: 0.69, 95% CI: 0.60–0.79, p < 0.0001) and DPP-4 inhibitors (HR: 0.77, 95% CI: 0.68–0.88, p < 0.0001), after adjusting for age, enrollment year, sex, socioeconomic factors, health conditions, and past medication uses.”

Unpublished tests in C. Elegans confirmed the life-extension properties of several CCBs and GLP-1RAs at two concentrations:

Same for the impact on AD pathology:

Her conclusion:

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It’s interesting because Ora Biomedical also found that several CCBs increased lifespan such as nilvadipine 10 µM (+38.8%). However, not all CCBs increased lifespan in Ora Biomedical’s tests: Ora Biomedical Million Molecule Challenge Results - #229 by adssx

Other papers found similar results:

• Verapamil extends lifespan in Caenorhabditis elegans by inhibiting calcineurin activity and promoting autophagy 2020
• Benidipine calcium channel blocker promotes the death of cigarette smoke-induced senescent cells and improves lung emphysema 2023

Many papers also found that calcium channel blockers (and especially dihydropyridine CCBs) were associated with a lower risk of dementia compared to other antihypertensive drugs such as ACEIs and beta-blockers.

A trial of isradipine in PD failed but researchers are looking at intra-nasal delivery of isradipine now. There’s also an ongoing trial of nilvadipine for PD in Australia with results expected in 2025.

Amlodipine is by far the most used CCB in the world and it has the longest half-life so it seems best to control hypertension in humans. But do the life-extension properties extend to amlodipine? At which dose(s)? Are there better CCBs?

[dicarlo2]

How do these results compare to ARBs? Is it something unique to calcium channel blockers, or a general vasodilation/blood pressure reducing phenomenon?

[CronosTempi]

Disappointing wrt. SGLT2i in this protocol. I’m sceptical of aging clocks, the worm data is suggestive, and she mentioned that in the design the idea is to move from worms to mice. Frankly, I would find those results more interesting than worms, of course.

The problem with BP meds is what to do if you’re normotensive or nearly so. And if nearly so, you don’t have much of a margin to work with - what if even a lowish dose ARB like telmisartan brings your BP all the way down, so adding a CCB is not possible. Do you then substitute the telmi with a CCB? But the telmi seems to have documented benefits in humans - do we still drop it in favor of speculative life extension benefits for humans based on worm studies?

I guess those with naturally low BP are out of luck in this scenario. Can’t use BP meds. But then again, isn’t that true for all these interventions, where a percentage of the cohort do not benefit or even experience a negative, including rapamycin. Why should it be any different with these BP meds. Luck if the draw. It is always better to be lucky than good.

[adssx]

As far as I know, there’s no evidence that other antihypertensive increase lifespan. In any case, for hypertension the recommended treatment is ACEI or ARB + DHP CCB (for instance telmisartan + amlodipine).

@CronosTempi

Disappointing wrt. SGLT2i in this protocol.

Why? I think it’s just that they didn’t have enough data (SGLT2i are a recent class of drugs compared to GLP-1RAs).

@CronosTempi

The problem with BP meds is what to do if you’re normotensive or nearly so. And if nearly so, you don’t have much of a margin to work with - what if even a lowish dose ARB like telmisartan brings your BP all the way down, so adding a CCB is not possible.

My guess: If BP > 120 mmHg, you can give a try to telmisartan or amlodipine low-dose. If not: you don’t do anything and focus on other interventions?

[CronosTempi]

Yes, I think that is correct. Everyone probably has their own pathways to affect aging intervention. Maybe rapa doesn’t work for you, but CCB does. Or CCB and rapa doesn’t, but an anti diabetic does, and so on.

[adssx]

Yes. And at least for CCBs and GLP-1RAs we have a biomarker to follow (Hb A1c and SBP respectively). For rapa it’s a wild guess…

[AlexKChen]

amlodipine here - Amlip (Amlodipine Besilate) - United Pharmacies

[adssx]

FYI: Amlodipine lowered lifespan when Ora Biomedical tested it. I’ve sponsored a dose response to confirm the finding.

[Davin8r]

This is all the more interesting to me because of the potential positive interaction between a GLP med (which usually increases heart rate) and diltiazem (calcium channel blocker, which appears to be the only way to negate HR increase from GLPs), and the fact that both appear to reduce risk of dementia.

[PBJ]

Would a beta blocker lower heart rate from GLP medications? I understand it may not have the same AD benefits as a calcium channel blocker, but may lower HR and have cardiovascular and kidney health benefits.

[Davin8r]

@PBJ

Would a beta blocker lower heart rate from GLP medications?

No, BBs don’t appear to work for GLP med HR increases (from a recent in vitro study and from personal experience). See the discussion in the GLP experiences thread for more details.

[PBJ]

OK thanks, good to know. From what I saw looking into it, it said a beta blocker may lower increased HR from GLP’s. Once I combine an SGLT2i, I may try lowering my GLP dosage. My heart rate has increased some, but it also lowered due to weight loss.

[LukeMV]

I think it’s more important to remember how well SGLT2 drugs did in the UK biobank data that made headlines a while ago. I’d say that is more cause for optimism than this.

2024.03.08.24303967.full.pdf

Longevity Briefs: 14 Drugs That Might Extend Human Lifespan Are Already In Use...

[LukeMV]

Yea, Nebivolol has done zero to lower my RHR for that. Even increasing from my usual 5mg to 10mg didn’t help and lowered my diastolic BP too much.

@Davin8r

This is all the more interesting to me because of the potential positive interaction between a GLP med (which usually increases heart rate) and diltiazem (calcium channel blocker, which appears to be the only way to negate HR increase from GLPs), and the fact that both appear to reduce risk of dementia.

I was just thinking the same. Now I am even more encouraged to try out a low dose of Diltiazem (or verapamil only because I have some sitting around unopened). I think I’ll try it on a day I do not plan to exercise in case it makes me tired as I have never taken a CCB before.