Aging at the cellular level is called “cell senescence”, and it contributes profoundly to whole-body aging.  The most promising near-term prospects for a leap in human life expectancy come from drugs that eliminate senescent cells.  Programs in universities and pharmaceutical labs around the world are racing to develop “senolytic” drugs, defined as agents that can kill senescent cells with minimal harm to normal cells.

Apoptosis is cell suicide, and (from the perspective of the full organism) it’s the best thing that can happen to senescent cells.  The authors of this newest Dutch study ask how it is that senescent cells escape apoptosis.  

FOXO is a protein that controls gene expression, a master transcription factor associated with aging and development.  (It is the homolog in mammals of the pivotal life extension protein first identified in worms as DAF16 in the 1990s.)  FOXO4 activiation in a cell can block apoptosis.  P53 is the most common trigger of apoptosis, the first protein biochemists usually think of in connection with apoptosis.  P53 has multiple functions in the cell nucleus, but as a trigger for apoptosis, it works through the mitochondria.  FOXO4 binds to p53 and blocks its induction of apoptosis.

The treatment studied in this paper is an artificially modified FOXO4, a dummy that binds to p53 in place of regular FOXO4, but doesn’t block senescence.  It has been named FOXO4-DRI, and it works by crowding out the native FOXO4.

The authors note, with caution, that mice with no FOXO4 at all appear normal; but apoptosis is an important cell function throughout the lifespan.  A cell must have “good judgment” about when to eliminate itself, and that works in both directions; in older animals and people, we not only see failure of apoptosis to eliminate senescent cells, but we also see healthy muscle and nerve cells undergoing apoptosis prematurely, and we lose muscle and brain mass as a result.  Other functions of FOXO4 include DNA repair, and mice that lack FOXO4 are subject to a high burden of DNA damage.

By analogy with chemotherapy for cancer, the value of a senolytic treatment is measured by its ability to kill senescent cells without doing harm to normal cells. The index called SI50 (SI for “selectivity index – 50%”) is defined by analogy to LD50 = the “lethal dose” of a toxin, the dose at which half of all cells die.  SI50 is defined as the ratio of LD50’s for normal and senescent cells.  It is the concentration of the agent at which half the normal cells die, divided by the concentration at which half the senescent cells die.  Authors of the current paper report SI50 about 12.  My guess is that 12 is an encouraging beginning, but it is not high enough to support a useful therapy.  After a standard dose is injected in humans, the cellular concentrations vary from person to person and from tissue to tissue. 

The encouraging fact is that, at the optimal dose, more than 80% of the senescent cells have succumbed to apoptosis, while the number of eliminated normal cells is still below detection:

In other words, the vertical distance between the black and red curves is encouraging, but the horizontal distance is cause for concern.  Senolytic agent studied previously, including dasatinib, quercetin and ATTAC, did not include measurements of SI50 that we might use for comparison.

 

How does FOXO4-DRI perform in live mice?

Authors of this study were excited in a rush to publish.  They used a fast-aging strain of mice, and even for these, they did not wait to see survival curves.  The indicatators of rejuvenation that they do report look positive:  increased activity levels, regrowth of lost fur, and improvement of kidney function lost with age.

 

Comparison to Last Year’s Senolytic

Here’s how authors of the current study characterize FOXO-DRI compared to two previously reported senolytic agents:

Two classes of anti-senescence compounds have been reported so far: Quercetin/Dasatinib, either alone or in combination [ref], and the pan-BCL inhibitors ABT-263/737 [ref, ref]. Quercetin and Dasatinib have been reported to be non-specific. We found no selectivity toward senescent IMR90 and therefore this cocktail was not explored further. ABT-263 and ABT-737 target the BCL-2/W/ XL family of anti-apoptotic guardians. Indeed, ABT-737 showed selectivity for senescent IMR90. However, already at low doses, it appeared to influence control cells as well. Also in a treatment regimen where both compounds were added in consecutive rounds of lower concentrations, FOXO4-DRI proved to be selective against senescence yet safe to normal cells.

I reviewed the Quercetin/Dasanatib paper two years ago.  It was an early proof-of-principle, using medications that are already known (and FDA approved).  But the 1-2 punch is not sufficiently selective–it is toxic to normal cells.

I missed the two papers about ABT-263  [ref] and ABT-737  [ref].  BCL-2 is the founding member of another family of proteins that signal a cell to resist apoptosis.  Both ABT-263 and ABT-737 were identifed in screens for agents that block BCL-2.  These two studies published in Nature last year, one from University of Arkansas, the other from the Weizmann Institute, both use radiation exposure to create a large population of senescent cells, and then show that the senescent cells are selectively eliminted by ABT.  The ABT-263 paper included some in vivo results, indicating enhanced growth of blood stem cells after senescent cells have been removed.  In vivo testing of ABT-737 was limited.  Neither group reports the selectivity index (SI50) as calculated by Keizer in the latest study; but from graphs that they do present, it is clear that ABT-263 is more selective than ABT-737, and that neither is as selective as FOXO-DRI.

The original marker used to identify and target senescent cells by the Mayo Clinic’s 2011 study was p16^Ink4a.  The selective elimination technique they used (in 2011) was limited to genetically modified mice, but a year ago, a new paper from Mayo Clinic demonstrated a similar procedure for ordinary, non-GMO mice.  Twice weekly injections of an antibody that induced apoptosis in cells that expressed p16^Ink4a extended lifespan of the mice by 25% – 30% compared to controls, comparable to the results in the 2011 paper.  Caveat: the control mice received sham injections that shortened their lifespans.

 

The Bottom Line

The idea of removing senescent cells has a lot of appeal.  Not only does it enjoy broad empirical support in mammals; it also pulls together several ideas about the origin of aging:

• Parabiosis experiments and their follow-ons have convinced us that circulating chemical signals form the basis of an epigenetic clock.  Some of these circulating molecules are known to come from senescent cells.
• Aging commonly accelerates exponentially with age, as though it were driven by a positive feedback loop.  Senescent cells secrete cytokines that make more senescent cells–there’s your feedback.
• Short telomeres initiate senescent cells.  At any given time, there is a bell-shaped curve of telomere length among the body’s cells.  The tail of the telomere distribution contains a few cells that are driven to senescenceby having very short telomeres.

There is now a world-wide effort, making rapid progress toward specifity in senolytic treatments.  In other words, FOXO-DRI is the newest agent, and it shows the best ratio yet for killing senescent cells while avoiding collateral damage to healthy cells.  (It cannot be taken orally and must be injected, but perhaps this is not such a great drawback for a treatment that is needed only intermittently, every few years.)

How will such promising mouse results translate into human health and life extension?  We have as yet no data, not even anecdotes.  But perhaps we are near the point where hope and courage will motivate the first self-experimenting volunteers.  Caloric restriction and its mimetics produce much greater percent increases in lifespan in mice (2 year lifespan) compared to dogs (10 yrs) or monkeys or humans.  Senolytics work via a completely independent pathway; we can hope that percent benefits in humans will be closer to the mice.  Since this is about upregulating elimination of cells via apoptosis, the strongest benefits are likely to be against cancer, and mice are more vulnerable to cancer than humans.

This is a fast-moving field in which researchers are in a rush to publish and (presumably) pharmaceutical companies are taking pains to keep their results hushed up.  Sharing of information and resources could push this research over the top and give us the first full decade of human life extension.

Yes, there are too many reports the last few years of people announcing the end of aging.  But this, I feel, is the first time a drug has been discovered that has the potential to extend our lives by decades, with a few injections.

Background: As we get older, some of our cells become ‘senescent’.  They don’t just fall down on the job; they send signals out to the body which make us old and (especially) promote inflammation, leading to higher rates of cancer, heart disease and AD.  There are very few senescent cells—perhaps one in 10,000.  But they do enormous damage.

A few years ago, Jan van Deursen of Mayo Clinic showed that by killing off the senescent cells in mice, he could make them live 25% longer.  This was done with a drug, but the catch was that the mice were genetically modified.  Each senescent cell had a bomb in it, and all it took was delivering a trigger.  The treatment only worked if the mice were specially prepared (before birth) with this genetic modification.

This was 2011.  University labs  and drug companies around the world took appropriate notice, and they started working on ways to kill senescent cells without harming normal cells that would work in animals (including you and me) who have not been prepared ahead of time with bombs in their senescent cells.

Yesterday, scientists from the Netherlands announced successful deployment of a magic bullet that would kill senescent cells only.  It works in cell cultures, and it works as an injection in mice that have short lifespans.  (They haven’t had time yet to test it in fully normal mice, but in theory, it should.)

It’s a large molecule that you can’t take in a pill, because your digestive system would dismember it.  But it can be injected, and one dose ought to be rejuvenating.  I expect that people will be lining up to try this within a year, and that the injections will turn out to be needed only once in every few years.

My previous article on the subject
Link to Science News article by Mitch Leslie
Research Article

Human Ageing Genomic Resources announced last week their on-line database of animal studies that evaluated drugs and supplements for extended lifespan.  HAGR is a project of the University of Liverpool, spearheaded by João Pedro de Magalhaes, who has been an activist-scientist in aging research since his days as a grad student at Harvard.

The database is a great resource for researchers, and helps assure that we have no excuse for overlooking a substance or a perspective or a particular result.  Maintaining and updating it will continue to be an important and demanding project.

The full database covers 1316 studies, and I will review here just those on mice and rats.  My reason is that life extension in simpler animals turns out to be too easy.  There is much we can learn about universal biochemistry from studies in worms and flies, but most of the successes there fail when the (longer and costlier) studies are done in mammals.

Here is a spreadsheet extracting just the 93 studies on mice and rats.  You can view it online, and if you download it or copy it into your own GoogleDrive account, you can sort and edit and re-arrange it at will.

 

Old News

Rapamycin: Has the most studies and the best data.  Clearly works, but has side effects and it is not yet clear if it is appropriate for general use.  Make your own decision.  [read more]

Metformin: We have extensive experience with humans, and clear indications that it lowers cancer rates and ACM*, but there are dangers and side-effects. [read more]

Melatonin: Good evidence for modest life extension in rodents. For some people, it’s also a good night’s sleep; for others it can lead to grogginess or depression.

Aspirin:  The best evidence for lower cancer and ACM* is in humans.  Most people can tolerate a daily mini-aspirin without stomach complications.  

Epithalamin (and other short peptides):  This is work by Anisimov in St Petersburg, and it is so promising that I can’t understand why it isn’t being replicated all over the world. [read more]

Deprenyl:  Old studies, but they show consistent, if modest life extension.  It affects CNS in ways that you might feel, might like or might not.  [read more]

Vitamin E:  This is just one study, dosage equivalent to hundreds of pills a day, mice kept in shivering cold conditions.  [ref]  In a large human study, antioxidant vitamins increased mortality. [ref]

Acarbose: A diabetes drug that blocks the digestion of carbohydrates.  Side effects and toxicity make it less promising than metformin as a general recommendation.  [drug info]

C60 Fullerene:  Just one study in 6 rats, with spectacular results.  Replication has failed [private communication from Anton Kulaga].  Nevertheless, there are thousands of people experimenting on themselves. [read more]

Curcumin: There are major questions about absorption and dosage, but no question that anti-inflammatories are a good general strategy, and curcumin is a good anti-inflammatory. [read more]

Green tea:  Small but consistent life extension from polyphenols extracted from tea.  From a number of high-profile experimentalists, 2013.

Resveratrol: Works great in simpler animals, including some vertebrates, but in mammals life extension has been limited to overweight mice on a high-fat diet. [read more]

 

The New Part

BHT:  This is an anti-oxidant and chelating agent, which means that it is attracted to metal ions, it pulls them out of circulation and takes them out of commission.  This sounds good when it’s removing mercury or lead, but less good when it’s removing iron and dangerous if it’s removing zinc or other essential trace minerals.  BHT has long been used as a food packaging additive to preserve freshness, and it is still avoided by natural foods types. This Russian study [2003] found 17% life extension in mice. 

Creatine:  Used by body-builders, it encourages muscle growth by blocking myostatin.  It also increases nerve growth, and slows shrinking of the brain.  In one promising mouse study [2008], average lifespan increased 9%.

Icariin: This is an active ingredient in the traditional Chinese herb which in the West is known as Horny Goat Weed.  One mouse study, 6% increase in lifespan.

VI-28: Another Chinese herb.  Just one study, up to 14% increase.

Royal Jelly:  Queen bees are genetically identical to worker bees, yet they live 100 times longer.  Is it the royal jelly they are fed?  One mouse study [2003] showed a 25% increase in mean lifespan, but no increase in max lifespan.

N-Acetyl Cysteine:  Glutathione is an antioxidant associated with mitochondria.  Unquestionably, glutathione is a good thing.  Too bad we can’t just eat it.  The next best thing is to take the precursor, NAC, which seems to lead to increased glutathione throughout the body. This one study [2010] came out of the same prestigious group at Jackson Labs that brought us rapamycin.  Mean lifespan increased a stunning 25%. Two reservations: (1) they used enormous dosages, and (2) the mice on high-dose NAC ate less, so they probably benefited from caloric restriction.

Ginkgo biloba: Extract from the stinky fruit of an ancient oriental tree.  Traditionally used as a neuroprotective and concentration enhancer, for which it is mildly effective.  In 1998, a single study found 17% life extension in rats.  Who knew?

 

The Bottom Line

Clearly there is a great deal of promise here, but there is also much work to be done before we have it sorted out.

• Many treatments have shown promising results in just one study, and that needs confirmation.  My top priorities would be epithalamin, NAC, and royal jelly.
• Other treatments inspire enough confidence that we should be optimizing dosage for human use.
• As I have written, the most important work before us now is to see how these different treatments combine.  Most combinations won’t work together, but when we find the few that synergize we will have a candidate protocol for major life extension in humans.

If you’re curious, of the substances reviewed here, I personally take metformin, aspirin, creatine and NAC.  I season with turmeric a few times a week.  I have dabbled with deprenyl and rapamycin.

———————

* All-Cause Mortality

 

At different times, I have written about 8 different anti-inflammatory supplements, including aspirin, ibuprofen, omega 3 oils, curcumin, berberine, resveratrol, ashwaghanda, and boswellia, in addition to eating foods such as ginger, rosemary, tea and several mushroom species with anti-inflammatory effects.  There is good evidence for benefits from each of these individually, but I have no idea how they interact with one another.  Just last week, I learned that they all act (in part) through inhibition of NF-kB.

It’s certain that the separate benefits of each of these don’t just add up in combination.  It could be that all of them together are no better than just one of them individually.  It might even be that they interfere destructively with one another, competing for a common receptor, so that piling on more supplements is counter-productive.  There is no research on interactions among longevity supplements.

 

Prelude

In this (2007) study, a multidisciplinary team performed a systematic search for blood factors that change most consistently with age over a sample of mammalian models, and organized these into modules that tend to vary in a coordinated way.  They then searched for transcription factors that can turn each module on or off.  Their most prominent finding was that NF-κB turns on the suite of factors characteristic of old age.  Out on a teleological limb, they were bold enough to call it “Enforcement of aging by continual NF-κB activity” in the title of the article.  (In this perspective, senescence is an active process, coordinated by the genome.  I agree there is good evidence for this.)

After a long path leading to NF-κB as their prime subject, the authors go on to test whether inhibiting NF-κB can have anti-aging effects.  The first obstacle that they encounter: NF-κB has important developmental functions (in young animals) and also is essential for regulating apoptosis (in older animals as well).  Mice with genes for NF-κB knocked out don’t survive gestation.  So they arranged to selectively “blockade” the binding of NF-κB to DNA in old mice, in skin cells only.  The result was a dramatic rejuvenation of the skin.

 

Background

Research with rodents and humans suggest that there are factors in the blood that keep us young and, more important, factors that make us old.  Prime suspects in the latter category are the signals that dial up inflammation.  It’s my hunch that the most effective anti-aging strategy over the next 10 years will be to re-adjust signal molecules in the blood, adding what we lose with age but, more important, neutralizing or inhibiting pro-aging factors.

For various reasons, NF-κB is a good place to start.

“NF-kB has been termed the central mediator of the immune response. Gene knockout and other studies establish roles for NF-kB in the ontogeny of the immune system but also demonstrate that NF-kB participates at multiple steps during oncogenesis [ref] and the regulation of programmed cell death [ref].” [John Hiscott]

It is a complex of different molecules that acts as a master transcription factor.  It is always resident in the periphery of the cell, waiting so that it can be activated quickly when needed.  Latent, NF-κB is bound to an inhibitor molecule called IκB.  When a stimulus comes along that phosphorylates the IκB, the NF-κB is freed to enter the cell nucleus and switch on a variety of different genes, which varies from one cell type to another.  The best-known activity of NF-κB is in white blood cells (T and B cells) where it activates an inflammatory response  involving TNFa and IL-6.  Overactivity of NF-κB with age is a mediator of the systemic inflammation that contributes so much to cancer, heart disease and dementia.

NF-κB itself is not circulated in the blood, but signals in the blood can cause it to be turned on.  The Conboys early recognized NF-κB as one of the pathways that promote aging in parabiosis and transfusion experiments, where blood from older mice is introduced into younger mice.  It is a very good bet that inhibiting NF-κB would slow inflammaging, perhaps relieving arthritic and other auto-immune symptoms immediately, while reducing long-term risk of mortality and disease.

 

Inflammaging and Auto-immunity

Exponential amplification is a basic principle of the body’s immune response.  When the signal is received announcing an invader or an infection, there are just a few cells involved.  These send signals that trigger an immune response in other cells, triggering a chain reaction.

The beauty of such a system is that it ramps up quickly, and can mobilize a response throughout the body in short order.  This is also the danger of the system.  It requires an accurate and reliable switch to turn it off; otherwise, it can become like the Sorceror’s Apprentice, each magic broomstick producing two more to carry water until the workshop is flooded.

Note:  Dr. Katcher, in a note below, makes an important point about this positive feedback loop.

• Senescent cells  spit out inflammatory cytokines
• This activates NF-κB, which blocks apoptosis that could get rid of the senescent cells.
• Inflammation from NF-κB turns more cells senescent, beginning the cycle over again.

NF-κB is a master switch that sets in motion a chain of events that is specific to a cell type and its environment.  Some auto-immune diseases (e.g., arthritis, type 1 diabetes, asthma, Crohn’s disease and irritable bowel) are associated with an excess of NF-κB [ref].  Its activation generally rises with age [in mice, in humans], but it is necessary at all ages, particularly for its contribution to the regulation of apoptosis (the selective elimination of cells that are potentially damaging).  Animals lacking NF-κB are not viable; so it will probably be necessary to strongly but selectively inhibit NF-κB, beginning in middle age.

Inflammatory responses are complex and focused on the immediate threat at hand.  NF-κB is a master switch that sets in motion a chain of events that is specific to a cell type and its environment  It’s true that without NF-κB this response doesn’t happen, but the response to NF-κB varies from cel to cell.  In this sense, inhibiting NF-κB is a kind of blunt instrument.  It works to damp the body’s inflammatory response globally, but even better would be if we could selectively shut off the body’s attack on itself.  It’s true that NF-κB activation rises with age [in mice, in humans].  But the real problem is not too much NF-κB expression, but the fact that NF-κB becomes defocused, so that the inflammatory response is not focused on a particular threat, but generalized throughout the body [ref].

Here’s an angle I learned about recently from Steve Cole:  While inflammation is an important defense against bacterial infection, it is actually counter-productive against viruses.  Inflammation can create an environment that invites viral infection, perhaps because apoptosis is suppressed.  (NF-κB suppresses apoptosis.)  Viruses aren’t so dumb, and some of them have learned the advantage of promoting NF-κB.  Some of the reason that NF-κB is upregulated with age may be a residue of chronic viral infections.  [Hiscott, again]  (Just to confuse us, NF-κB can also promote apoptosis in other contexts.)

 

Two pathways

All the anti-inflammatory agents that I have been able to catalog work by one or both of these two pathways:  NF-κB and COX2.  By most accounts, NF-κB is upstream of COX2, but the two are interrelated.  NF-κB regulates COX2, and also COX2 feeds back to regulate NF-κB.

NSAID drugs (aspirin, ibuprofen, naproxen, celecoxib, etc.) target cyclooxygenase-2=COX2.  Common herbal anti-inflammatories, including curcumin, resveratrol, vitamin D and omega 3 oils (the last two not exactly herbs) are active both against COX2 and NF-κB.  Inhibiting COX2 is a classic strategy for combatting arthritis.  The more potent COX2 inhibitors have a tendency to decrease cancer risk, while increasing cardiovascular risk.  This doesn’t necessarily mean, “it’s a wash”–rather the stronger NSAID’s are right for people with some genetic risk profiles and should be avoided by others.  Aspirin is the cheapest and oldest of the NSAIDs, for which there is copious data available on tens of millions of individuals.  There is reasonably good evidence that aspirin leads to lower heart risk as well, probably because of anti-clotting rather than anti-inflammatory action [read more].  Daily aspirin also lowers risk of several cancers.

 

Inhibiting NF-κB

Intermittent fasting or caloric restriction tends to prevent NFκB binding to chromosomes..  There’s also a long list of natural products that inhibit NFκB.

source of this chart

There are a few pharmaceutical products that inhibit NFκB, though none has been developed explicitly for this purpose.  These include emetine, fluorosalan, sunitinib malate, bithionol, narasin, tribromsalan, and lestaurtinib.  Emetine (as the name suggests) is used to induce vomiting and also to treat amoebic diseases.  It is the most potent inhibitor of NFκB among the listed drugs.  Sunitinib and Lestaurtinib are cancer drugs. Bithionol is used in de-worming animals. Narasin is an uncommon antibiotic. Tribromsalan is used externally as an antiseptic. None of these is marketed to inhibit NF-κB, and none have (to my knowledge) been tested for anti-aging properties.  The larger pool of prescription drugs that affect NF-κB are all steroids.  For example, dexamethasoneis a glucocorticoid (steroid) drug that was one of the earliest inhibitors of NF-κB to be discovered.

Many items in the list of natural products have multiple benefits. Silymarin has been reported to promote telomerase.  Rosemary and cloves protect against infection.  Berberine helps maintain insulin sensitivity, and was found to be as good as metformin in one test.  Tea polyphenols and resveratrol have been promoted as generally anti-aging.  Too much has already been written about curcumin.

New to me in this list is celastrol, an ingredient in thunder god vine (Tripterygium wilfordii).  This is a Chinese herb (leigong teng = 雷公藤), that has been prescribed for centuries in formulas to relieve arthritis, along with lupus, MS and other autoimmune disorders.  It is reported to be a powerful appetite suppressant and weight loss aid.  The trouble is that it is toxic, and the thunder god root must be prepared carefully in order to exclude triptolide, which is yet more toxic.  Experienced practitioners of traditional Chinese medicine know how to mix with other herbs and control dosage to minimize side-effects.  In the absence of this kind of expertise, I can only counsel experimenting gingerly with tiny quantities of thunder god vine in order to guage your personal response.

 

How important is inflammation?

It would be interesting (from a theoretical and a practical vantage) to know what is the maximum benefit available from manipulating the inflammatory pathway.  Inflammaging is linked to all the diseases of old age.  Suppose we dialed the systemic inflammation in a 80-year old back to where it was when he was 20, but we made no other change in the body.  What would be the effect on mortality and morbidity?  On vitality, resistance to infection, and stamina?  In other words, how much of the aging process is directly attributable to inflammation?

We might try to get a handle on this question via an epidemiological calculation: What is the correlation between inflammation and all-cause mortality?  If we extrapolate back to the inflammation level of a 20-year-old, how far does that go toward restoring the mortality rates of a 20-year-old?

We might think to look at genetically modified mice without NF-κB; however, they die in utero.  (There are no pure aging genes; aging is caused by re-balancing hormones and proteins, all of which have life-supporting as well as life-denying functions.)  There is a genetic variant of NF-κB that tends to be more common in centennarians than the rest of us [ref].

 

How much does inflammation rise with age?
Erythrocyte Sedimentation Rate and C-Reactive Protein

120 years old, the ESR test is still the most basic (and cheapest) measure of systemic inflammation.  The quantity measured is the number of red blood cells that clump together and fall out of solution in one hour.  Inflammation makes red blood cells sticky, and I’ve seen two explanations for the reason.  One is that fibrinogen, the clotting protein, rises with inflammation; the other is that the negative charge (zeta potential) naturally associated with oxygen-carrying red blood cells decreases with inflammation, so there is less mutual electrostatic repulsion.  The increase in blood’s tendency to clot that is associated with inflammation is part of the reason that inflammation is a risk for heart attacks and stroke.

C-Reactive Protein is a protein created in the liver as part of the response to inflammation.  It is easily measured with an antibody, so it has become the second most common blood test for inflammation.

ESR rises with age, but not dramatically compared to interpersonal variation:

 In fact, the difference between women and men is more than the difference between an 80-year-old and a 20-year-old of either sex.  Increase in CRP with age is even more subtle.  (This article claims it doesn’t rise at all, in a small sample of <400 patients.)

This article claims that CRP does rise with age (using a sample of 21,000):

A Glasgow study of 160,000 patients found strong correlation between CRP and near term mortality (within a year, HR=20) but not much for longer term. This is not what I was expecting.

In 26,000 patients, inflammatory markers were associated with a 1.5-fold increase in all-cause mortality (ACM) over 8 years.

A Norwegian study of 7,000 men and women found that high levels of CRP raised ACM only by a factor 1.25 (equivalent to just 2 years of aging).  For comparison, the ACM risk for an 80-year-old male is 60 times higher than a 20-year-old male.  The corresponding number for females is nearly 120.

The implication is that either inflammation is a minor (though significant) cause of mortality, or else the markers that we have for inflammation (including ESR, CRP and leucocytes) are not capturing the rise in systemic inflammation.

Hint: “Centennarians, on the other hand, manage to stave off these deleterious sequelae.Despite signs of inflammation, such as high levels of interleukin-6 (IL-6), fibrinogen, and coagulation factors, they are remarkably free of most age-related diseases that have an inflammatory component.” [ref]

 

NF-κB in the Brain

It is my favorite hypothesis that aging is mediated through hormonal signaling, under control of a clock in the neuroendocrine regions of the brain.  So I am interested in changing NF-κB activity in the aging brain.  This paper describes roles for NF-κB in brain development, regeneration after injury, and also evidence that NF-κB can be activated in response to nerve signals.  In the other causal direction, neural signaling (and presumably behavior) can change in response to NF-κB.  Directly on target (in my book) is this paper from Nature (2013). “By systematically controlling NF-kB activity in the hypothalamus alone, the authors are able to increase the healthspan as well as the lifespan of mice.”

 

The Big Picture

In the Prelude above, we found evidence that NF-κB is a master regulator that turns on a suite of genes that “enforces aging”.  But in the section, How important is inflammation?, we found evidence that, while inflammation certainly increases with age, the increase is not large compared to the scatter among individuals.  Centennarians commonly have high levels of inflammation, along with robust health.  Large increases in inflammation are common just in the last year of life, but they are not well correlated with the gradual increase in mortality with age.

The combination of these two findings suggests that NF-κB has other powerful roles in promoting senescence, in addition to its well-known role as effector of inflammation.  Maybe it is a master regulator of development and aging, akin to mTOR and FOXO.  It is a hypothesis worth testing that carefully tailored inhibition of NF-κB is a life extension strategy, so long as we can preserve apoptosis at an appropriate level.