Inflammation as a Key Target for Longevity

#1

IMO: In this forum, we seem to be more obsessed with lowering cholesterol than lowering CRP.
This, I think, is a mistake. Also note that CRP is included in the Morgan Levine chronological age clock; cholesterol is not.

Below are the edited responses from ChatGPT 5 (paid).
If anyone wants to see the complete, more nuanced response, plug the queries into your favorite AI program.

Query: 'Which do you think is more damaging to healthspan and lifespan, high cholesterol levels or chronic inflammation?"

Answer: “Short answer: chronic inflammation is probably more fundamentally damaging, but in real life, it’s usually the combination of high cholesterol (especially apoB/LDL) plus chronic inflammation that does the most harm to healthspan and lifespan. If I had to choose one axis to obsess over for someone with heart disease, I’d actually say, “High apoB/LDL in an inflamed environment is the real killer.”
So: treat both; don’t pick a favorite.”
Chronic inflammation – why many people now see it as “more fundamental”

Chronic, low-grade inflammation (often measured by hs-CRP, IL-6, TNF-α, etc.):
Is associated with:
CVD events independent of LDL.
Frailty, sarcopenia, cognitive decline, diabetes, and overall mortality in older adults.
Trials like CANTOS (canakinumab) and COLCOT/LoDoCo2 (low-dose colchicine) showed that targeting inflammation in people with already low LDL still reduces heart attacks and strokes.
That tells us inflammation is not just a bystander.
In aging medicine, we sometimes talk about “inflammaging”:
Chronic inflammatory tone gradually:
Damages vessels.
Impairs immune function.
Interferes with repair processes.
Promotes insulin resistance.
It’s plausibly involved in neurodegeneration, cancer promotion, osteoporosis, and frailty, not just clogged arteries.
So while high LDL is mostly about vascular risk, chronic inflammation hits many organ systems at once. That’s why many longevity people would say: if you forced them to pick a single underlying villain, inflammation is “more global”.

Query: “What blood test best measures inflammation?”
Answer: High-sensitivity C-reactive protein (hs-CRP) – the longevity favorite

What it measures: A liver protein that rises when the body is inflamed.
Why it’s favored:
Detects low-grade, chronic inflammation (values in the 0.5–10 mg/L range).
Strongly associated with cardiovascular risk and overall mortality, even after adjusting for cholesterol and other risk factors.

For someone interested in healthspan and lifespan, this is usually the single most informative, practical marker to track over time.

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#2

A lot of longevity treatments reduce inflammation as a side effect so it’s not really the focus.

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#3

Yes true, rapamycin reduces inflammation and senescence at the cellular level as a target of cell autophagy and repair.

My glycans measurements show that benefit over past 4 years.

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#4

So you are saying people are reducing their CRP levels because of their lifestyles and other interventions without directly doing them to lower CRP levels? How many forum members do you think are actually tracking CRP levels as opposed to cholesterol levels, as the CRP is not normally tracked by the basic blood tests that doctors usually prescribe?

Which ones are you referring to? And do you think a large percentage of the forum are doing them?
You need to know your CRP levels to determine if additional interventions are needed reduce CRP levels and what those interventions are.
The problem is there are many things that raise CRP levels, and if you are not measuring CRP levels, you may be at risk without knowing it.

1. Infections

Acute infections are probably the most common cause of a big CRP rise.

  • Bacterial infections (pneumonia, cellulitis, urinary tract infections, sepsis, appendicitis, etc.) can push CRP very high (often >50–100 mg/L).
  • Viral infections (flu, COVID-19, RSV, etc.) can also raise CRP, but often a bit less than severe bacterial infections on average.
  • Chronic infections (like tuberculosis, chronic sinusitis, some dental infections) can keep CRP mildly to moderately elevated for long periods.

2. Chronic inflammatory & autoimmune diseases

These often cause persistent, sometimes fluctuating CRP elevation:

  • Rheumatoid arthritis
  • Polymyalgia rheumatica
  • Systemic lupus erythematosus (SLE) – CRP can be less elevated than you’d expect; ESR is often more sensitive here.
  • Inflammatory bowel disease (Crohn’s, ulcerative colitis)
  • Vasculitis and other connective tissue diseases

CRP is often used to monitor flare-ups and response to treatment in these conditions.

3. Tissue injury, trauma, and surgery

Anything that causes tissue damage can raise CRP:

  • Recent surgery (often peaks around 48 hours afterward)
  • Trauma (fractures, major injuries, burns)
  • Heart attack (myocardial infarction) – CRP rises as part of the inflammatory response to heart muscle damage.
  • Intense muscle injury or rhabdomyolysis

4. Cardiovascular & metabolic risk factors

Even low-grade chronic inflammation shows up as slightly elevated high-sensitivity CRP (hs-CRP):

  • Obesity (especially central/visceral fat)
  • Metabolic syndrome & insulin resistance
  • Poorly controlled type 2 diabetes
  • Smoking
  • Sedentary lifestyle
  • Obstructive sleep apnea

These don’t usually give huge CRP spikes, but hs-CRP in the 2–10 mg/L range can be a marker of increased cardiovascular risk.

5. Cancers

Some cancers, particularly when advanced or causing tissue destruction, can drive up CRP:

  • Lymphomas
  • Solid tumors (lung, gastrointestinal, etc.)
  • Metastatic cancer of many types

Here, CRP is not diagnostic, but can correlate with disease burden or prognosis in some cancers.

6. Chronic organ diseases

Ongoing inflammation or damage in organs can keep CRP elevated:

  • Chronic kidney disease
  • Chronic liver disease (although severe liver failure may reduce CRP production because the liver makes CRP)
  • Chronic lung disease (COPD, bronchiectasis)
  • Congestive heart failure, especially when decompensated

7. Lifestyle and other factors

Smaller but real effects:

  • Smoking (again—worth mentioning twice)
  • Heavy alcohol use
  • Periodontal (gum) disease
  • Sleep deprivation
  • Chronic psychological stress
  • Obesity (central role in low-grade inflammation)

These often show up more clearly on hs-CRP than on standard CRP.

8. Medications and medical treatments

Some raise CRP indirectly by causing inflammation:

  • Certain drugs that cause hypersensitivity reactions or drug-induced autoimmune syndromes
  • Some chemotherapy agents
  • Radiation therapy (by causing tissue damage)

Others tend to lower CRP over time:

  • Statins
  • Some anti-inflammatory biologics (TNF-α inhibitors, IL-6 inhibitors)
  • Aspirin and NSAIDs (modestly, in chronic use)
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#5
#6

I think this may be somewhat correct, for the simple reason that heart disease / cardiovascular disease is the #1 killer of people in the developed world right now, lipid levels are commonly measured, and we have quite well proven ways to mitigate them.

We don’t have any numbers on how many people die each year from “inflammation”, to the best of my knowledge.

And, while Inflammation is a focus of mine, for example, and I have a HS-CRP measure of about 0.3, which is fine for now, but other measures like IL-6, IL-11, etc are more difficult and more expensive to get, and the precise actions we may want to take to lower age-related inflammation are more complex and unclear. There are no statin-like equivalents (or ezetimibe, PKSQ9 inhibitors, etc.) for inflammation.

So, I would agree, yes, it’s very important, but action plans (beyond staying “healthy” and getting in shape / exercising regularly, eating a “non-inflammatory diet”, etc. - are not so clear cut.

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#7

Going forward, I think this is the area we want to focus on, and why I think the Irisin productization will be interesting and important: Long-Acting Irisin With 30-Fold Longer Half-Life has Potent Anti-Inflammatory Effects

So, if we assume most of us here are pursuing the low hanging fruit in the area of inflammation (diet, exercise, etc,) the issue becomes “what’s next?” what are the new things coming down the pipe in the way of therapeutics that may help with inflammation. What will be the PCSK9 inhibitors of the inflammation world.

So I did this prompt:

Identify all the anti-inflammatory biologics (TNF-α inhibitors, IL-6 inhibitors) and also any clinical or scientific research suggesting that if healthy older animals people took these drugs it may improve healthspan and lifespan

Here is what CGPT5.1 came back with:

3. What happens when you give these drugs to aging but otherwise healthyanimals?

3.1 TNF-α blockade

Sarcopenia and survival (etanercept, aging mice)
Sciorati et al. (2020, Aging) treated C57BL/6 mice from 16 to 28 months with a TNF-blocking regimen (etanercept). Key results:

  • Prevented age-related loss of muscle mass and fiber size.
  • Preserved grip strength and performance in hanging-wire tests.
  • Reported improved overall survival vs controls (better late-life survival curves, though not a huge lifespan revolution). Aging-US

Paper: “Pharmacological blockade of TNFα prevents sarcopenia…”.

Gut motility / constipation (etanercept, old mice)

  • Patel et al. (Sci Rep 2017): old mice show decreased colonic SERT expression, altered mucosal 5-HT, and reduced fecal output. Chronic etanercept in old mice:

Paper: “The TNF-α antagonist etanercept reverses age-related decreases in colonic SERT expression and faecal output in mice”.

Cognitive function and cerebrovascular aging (etanercept, aged rats)

  • Gocmez et al. (2020, Physiol Behav): 24-month-old rats treated with etanercept:
    • Improved performance in memory tasks vs untreated aged rats.
    • Reduced peripheral and neuroinflammation, improved endothelial function and hippocampal BDNF levels. PubMed+2avesis.kocaeli.edu.tr+2

Paper: “Etanercept improves aging-induced cognitive deficits…”.

Neurodegeneration models (tauopathy / AD-like)

  • In PS19 tauopathy mice, chronic etanercept or a brain-penetrant TNFR fusion reduced microgliosis, phosphorylated tau, and hippocampal neuron loss; behavior improved but this is a disease model, not normal aging. BioMed Central+1
    – Ou et al., J Neuroinflammation 2021.

Bottom line for TNF in “healthy” aging animals
In naturally aged rodents, chronic TNF blockade:

  • Improves functional aging phenotypes (muscle strength, bowel function, cognition).
  • At least one study reports a modest survival benefit when started at mid-life.
  • These are small, lab-mouse studies with chronic injections; no multi-species or large-scale replication yet.

5. Direct answer to your question

Are there clinical or scientific data suggesting that TNF- or IL-6-blocking biologics could improve healthspan or lifespan in healthy older animals or people?

Animals

  • TNF blockade (especially etanercept)
    • In naturally aged rodents, chronic TNF inhibition can:
      • Preserve muscle mass and strength,
      • Improve bowel motility,
      • Improve cognitive performance,
      • And, in at least one study, modestly improve survival when started in mid-life.
    • That is legitimate healthspan improvement with suggestive lifespan benefit, but from small, single-lab studies.
  • IL-6 blockade
    • No convincing data yet that IL-6 or IL-6R antibodies extend lifespan in otherwise healthy animals. Nearly all work is in disease models.
  • IL-11 blockade (IL-6 family, but not TNF/IL-6 per se)
    • Strong mouse data: genetic or pharmacologic IL-11 inhibition from mid-life extends lifespan by ~20–25% and improves multi-organ aging phenotypes.

Humans

  • There are no trials giving TNF- or IL-6-blocking biologics to healthy older adults to improve healthspan or lifespan.
  • Indirect evidence from RA and other inflammatory diseases suggests:
    • TNF inhibitors do not increase overall mortality and may reduce cardiovascular events and Alzheimer’s risk compared with no biologic or csDMARDs, in inflamed patients.
    • IL-6 inhibitors effectively suppress inflammation and may increase lean mass in some RA cohorts, but with mixed cardiometabolic signals.

Translating that to primary prevention in healthy aging is speculative and, at present, unjustified given infection and malignancy risks.

6. Knowledge gaps and what would actually be needed

To seriously evaluate TNF- or IL-6-blockade as an “anti-aging” strategy, we’d need:

  1. Replicated, multi-center mouse studies
  • TNF and IL-6 biologics in naturally aged mice of both sexes, multiple strains.
  • Lifespan + deep phenotyping (frailty indices, epigenetic clocks, multi-omics).
  • Dosing regimens that mimic human exposures.
  1. Mechanistic work
  • How much of the benefit is sarcopenia vs neuroinflammation vs vascular vs gut barrier?
  • How does chronic cytokine blockade interact with infection risk and tumor surveillance in old animals?
  1. Carefully stratified human trials
  • Not “healthy 70-year-olds” out of the gate, but perhaps older adults with high inflammatory burden (e.g., high hs-CRP, multimorbidity) and no obvious autoimmune disease.
  • Short-to-medium-term trials using intermittent or low-dose regimens and multi-system aging endpoints (frailty scores, muscle function, imaging, epigenetic clocks), with very hard stopping rules for infection/malignancy.

Right now, IL-11 blockade is far ahead of TNF/IL-6 in terms of “pure” aging biology data in normal mice; TNF/IL-6 biologics sit in the “plausible but unproven” bucket for aging and are firmly disease-therapies clinically.

Full ChatGPT Response:

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#8

At the end of the day, both low CRP and low ApoB should be targeted. It’s not either/or.

Same can be said for blood pressure, Cystatin-C, GGT, A1C, and a few other biomarkers.

We can argue where to rank all of these in the hierarchy of which is most important, but there is really no excuse not to optimize all of these simultaneously. I think everyone would agree on that.

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#9

Since I began taking high-dose taurine, my CRP levels have shown a clear downward trend.

  • 2023-06-20: 1.1 mg/L
  • 2023-11-20: 1.2 mg/L
  • 2024-06-20: 1.3 mg/L

I started high-dose taurine in May 2024, taking 10 grams per day, all at once in the morning.

After about seven months on this regimen:

  • 2024-12-09: CRP dropped to 0.49 mg/L
  • 2025-05-21: CRP was 0.43 mg/L

Since then, I’ve taken a break from rapamycin and recently restarted at 6 mg/week (Rapamune). I’ve also reduced taurine to 5–6 grams per day. I plan to recheck CRP in the coming weeks.

So what caused the drop? Taurine is my prime suspect — it was the only major change I made before my CRP levels fell sharply — but it’s still unclear whether it’s taurine alone or a combination of factors.

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#10

It’s clear that inflammation is a significant factor in aging and lifespan, not to mention quality of life, for which maintaining good vision is priceless
Reducing inflammation may protect against early age-related macular degeneration-like vision loss
This is not really new information: The following reference is from 2005.
Progression of Age-Related Macular Degeneration: Prospective Assessment of C-Reactive Protein, Interleukin 6, and Other Cardiovascular Biomarkers | Cardiology | JAMA Ophthalmology | JAMA Network
wherein it is suggested that a CRP level greater than 0.5 is associated with at least a 3x greater rate of progession of ARMD
As is supported by:
Increased systemic CRP associated with choroidal thinning in intermediate ARMD
chen-rachel-increased-systemic-c-reactive.pdf

Additionally; regarding heart disease
Inflammation now predicts heart disease better than cholesterol | Empirical Health

Which is recognized by the American College of Cardiology
Inflammation and Cardiovascular Disease: 2025 ACC Scientific Statement: A Report of the American College of Cardiology - PubMed

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#11

If low-dose colchicine is good, febuxostat is better. Uric acid is itself inflammatory, and it spreads inflammation throughout the body. Allopurinol didn’t work for me, but febuxostat probably saved me from needing surgery.