Health

Reducing Senescent Cells to Slow Ageing

One of the hallmarks of ageing is the agglomeration of senescent cells.  Their abundant presence sets off our ageing mechanisms and with them our risk of developing some type of degenerative disease (type 2 diabetes, osteoarthritis, heart disease, cancer, etc).  If we can find a way to produce less senescent cells and have an efficient way of clearing out cells that have become senescent we may be able to slow down the ageing process.  In this article we will talk about what senescence is, how it ties in with NAD and telomeres, and how we may use natural products to kill off senescent cells.

What Is Sensence?

Senescent cells are popularly called zombie cells.  These are cells that are no longer working properly and cannot divide but they are not killed.  They secrete toxic substances like pro-inflammatory cytokines, chemokines, also proteases and some growth factors.  These secretions are referred to as SASP (senescent associated secretory phenotype).  The idea is that the immune system should quickly respond to these secretions and eliminate the senescent cells.  The senescent cells are useful as a defence mechanism against cancer.  Turning cancer cells into senescent cells stops them from reproducing and it sends out signals alerting the immune system to their presence.  Senescent cells are also how the embryo sculpts itself.  The cells that are to be taken away turn into senescent cells and are removed by immune cells.

The Problem With Senesence

However, when the immune system is not working properly and senescent cells are left for a longer period of time their toxic secretions will influence the microenvironment.  They may turn other, nearby cells into senescent cells as well, like we imagine that zombies do. If you think about how grey hairs form it is often in clumps where one cell affects the nearby cells.  The secretions of the senescent cells may affect the environment negatively.  Regeneration is stopped and a low-grade inflammatory process sets in.

 This low grade inflammation leads the way to most degenerative diseases like Parkinson´s, Alzheimer´s, cataracts, diabetes type two, osteoarthritis, glaucoma, some tumours, etc.  A low grade inflammatory process may also affect the expression of CD38, which may lead to lower levels of NAD (nicotinamide adenine dinucleotide) in the body, which may lead to poorly functioning Sirtuins, which are responsible for silencing the ageing process and repairing damaged DNA.

Over time, as we age, senescent cells tend to accumulate in the body and with them the ageing process is speeded up and the probability of degenerative diseases setting in.

How Do Cells Become Senescent?

There are different external and internal stimuli that lead to senescence.  One is telomere erosion, or replicative senescence.  Others are accumulation of reactive oxygen species (ROS) inside the cell, leading to damaged organelles like mitochondria damage that leads to greater ROS production or oxidation of DNA.  There may also be other stress-related phenomena from the outside, such as neighbouring senescent cell secretions promoting inflammation.

There are some proteins that are related to senescence. The major one is p53, which is also called the tumor suppressor.  It can activate DNA repair, or initiate apoptosis or senescence.  By inducing apoptosis or senescence in cancer cells it suppresses tumor growth.  Two other that are involved in some of the pathways leading to senescence are p16 and p21.  There are some scientists working on targeting these pathways, so that they may be inhibited and senescence may be reduced.

 

Telomeres and Senesence

One essential mechanism that leads to senescence is telomere dysfunction.  Telomeres are the repetitive sequences of nucleoproteins at the ends of chromosomes (TTAGGG in humans).  They are often likened to the end caps of shoelaces.  If the end caps are not there, the shoelace flares.  Similarly, if the end cap of the chromosome is critically short, it will lead to telomere dysfunction, which eventually leads to senescence and is associated with all sorts of degenerative diseases.

How Do Telomeres Become Shorter?

When we are born we have 5000 – 15 000 base pairs of telomeres.  As cells divide and due to certain influences we tend to loose an average of 70 per year.   A mitotic cell, meaning a cell that can divide and replicate itself, can usually divide around 60 times before its telomeres become to short.  This is called the Hayflick limit.  At that point, to prevent DNA damage, the cell will move into senescence.   This is called replicative senescence.  Even cells that are post mitotic, meaning do not replicate through division but need help from stem cells to regenerate tissues, like neurons or heart cells, can go into senescence if their DNA is somehow compromised due to other problems.

The more oxidative stress and chronic inflammation we have, the quicker we loose our telomeres.  This leads to a negative downward spiral, where the shorter telomeres lead to more senescence, which leads to more inflammation, which leads to shorter telomeres, etc.

The age silencing genes and DNA-reparing enzymes are also involved in this spiral.  

We now know that telomere dysfunction leads to the activation of p53, which leads to senescence, and which also leads to the inhibition of all sirtuins (age silencing genes).

However, if we can boost our NAD (nicotinamide adenine dinucleotide) levels we can activate the sirtuins and they will in turn stabilise the telomeres as well as inhibit p53.  Read more in our article about NAD and how to boost it here.

Here is a list of activities that all lead to a quicker shortening of telomeres:

  • Alcohol
  • Smoking
  • Lack of sleep
  • Chronic stress
  • Inflammatory diet

 

How Can We Stabilise and Grow Our Telomeres?

As we already mentioned above, boosting our NAD levels can help stabilise our telomeres and put us on an anti-ageing route, where inflammation is reduced and further telomere break-down is slowed down.

To grow our telomeres we can also use an enzyme called telomerase.  Some stem cells are quite rich in telomerase and when they divide they do not get shorter and shorter telomeres because the telomerase quickly rebuilds them.  There are ways of activating telomerase and substances we can take to activate it for cells other than stem cells.  The perhaps best known substance is from Astragalus Membranaceus.  Astragalus root has been used in Chinese Medicine for immune system boosting, longevity, and number of other conditions.  Since around 2008 there an extract of it called TA-65 has been available.   This focuses on a particular substance found in Astragalus called cycloastragenol and has been developed so that it has increased bioavailability.  This has been shown to lengthen telomeres.  In a one year study of people aged 53-87 years old a low dose of 250U of TA-65 increased the telomere length by an average of 530 basepairs (while the control group lost 290 bp).  Another study looked at a series of health markers (glucose, insulin, cholesterol, and blood pressure) for people taking TA-65 over five years and showed positive results.  However, it is rather expensive and can cost around 400 USD per month.

Recently a study has come out comparing TA-65 with an astragalus vitamin mixture, some other compounds, as well as Centella Asiatica (Gotu kola).  Interestingly enough, the astragalus vitamin mixture seems to be a little more effective than TA-65 but the Centella Asiatica is several orders more effective.  This will need to be verified in actual humans, inside of the body, but is quite interesting.

There is a company working on anti-ageing technologies that involve exosomes.  For therapeutical use these are usually vesicles from stem cells.  These are particularly interesting as they contain the information for cells that tells them to grow, but are not fully developed cells, and so there are no issues of rejection.  Liz Parrish, the CEO of BioViva had them administered and measured her telomeres.  When she was at the chronological age of 45 years old her telomeres were already at age 60.  After undergoing the treatment she restored them back to her chronological age, adding some 600 basepairs. She was scanned for cancer, as excessive telomerase activation is a present in cancer, but she was free of it.

Exosomes are interesting in regenerative medicine, as they can help regenerate tissues that normally have difficulty with it (like joints, nerves, etc).  A very interesting physician that works with this and other regenerative therapies (including NAD) and has been able to achieve surprising results is Matthew Cook.

It has been shown that meditation leads to longer telomeres.  Some studies focus on 20 minutes of daily meditation and show a lengthening of telomeres within 4 months.  Other studies show that meditators tend to have longer telomeres than what would be expected for their chronological age.  We know that mediation is related to stress reduction.  And so, perhaps this is one of the reasons why it works.

It has also been argued that an open heart, or feelings of love, are capable of lengthening telomeres.  Indeed, we do see positive results from studies done on loving-kindness meditation.

Can We Measure Telomeres?

It is at present possible to measure telomeres commercially in blood, in the leucocytes.   These re-new every 4 months, and so if one were to take a test, do an intervention, and then test again to see the effects it is good to wait at least 4 months before taking the second test.  These tests are expensive and run around 450 USD.

It may be interesting to know the average length of the telomeres but an even more interesting number to look at is the percentage of critically short telomeres.  This is because it is the critically short telomeres that can lead to senescence, and thereby quickly lead to a poisoning of other nearby cells.

Telomeres are sometimes seen as a way to measure biological age.  However, they are not the best biological age clock we have.  Methylation clocks seem to be more precise and efficient.  They can even predict our natural death with a high degree of accuracy.  The most accurate epigenetic clock is perhaps the GrimAge clock by Horvath and Lu.

Killing Senescent Cells

The body has was of killing the senescent cells and there are things we can do to activate those pathways.

Fasting

A natural way of increasing the removal of senescent cells is to increase the process of autophagy.  The most efficient way is to fast and to fast for about 5 days.  This will give the body time to go into deeper forms of fasting and macroautophagy.  It will reset the immune system, which will become even more efficient when it comes to clearing senescent cells.

AMPK Activation

What is AMPK?

AMPK (Adenosine monophosphate kinase) is the energy sensor or metabolism regulator.  It is regulated by the ratio of AMP/ATP (Adenosine monophosphate/Adenosine triphosphate).  ATP is how most cells store energy.  So, this means that when ATP is low, when there is little energy stored, AMPK is activated.  In that sense it is an “energy sensor”.  When energy is lacking, it is activated.  But this is not the only case.

You can take certain substances that make the body believe that there is a lack of nutrients and thus activate the AMPK pathway, which in turn will activate autophagy.  To do this a series of natural substances that can do this to some degree.  One of the most potent is berberine and then you also have alpha lipoic acid, EGCG (from green tea), curcumin, ginger, quercetin, resveratrol, apple cider vinegar DHA, EPA, creatine, ginseng, bitter melon, bergamot etc.

Activation of AMPK:

  • Fasting
  • High intensity training
  • Certain substances like berberine etc.

Suppression of AMPK:

  • Inflammation

Benefits of AMPK activation:

  • Activation of Autophagy
  • Stimulation of Sirt1 (which reduces inflammation)
  • Stimulation of FOXO (which also reduces inflammation)
  • Rapid release of energy and low blood sugar

 

It is good to activate AMPK regularly, but also have times, especially after exercising, when you give the body plenty of nutrients and stay away from the AMPK activating substances, so that the body may switch over and activate mTOR and thus build muscle more efficiently.

Sidenote on mTOR

mTOR is the mechanistic (or mammalian) target of rapamyacin and was discovered at some point in the 1960´s.  It activates our ability to build muscles by stimulating protein synthesis.  However, it simultaneously seems to de-activate AMPK and autophagy.  It leads to quick growth, but is not healthy as a permanent state.  mTOR is activated by protein consumption, particularly argenine and lucine.  When AMPK is activated it tends to inhibit mTOR.  It is usually a healthy option to have AMPK activated much more than mTOR.  However, mTOR activation is important, especially for older persons, which is one of the reasons why persons over the age of 65 are recommended to eat a little bit more protein.

Combining AMPK with mTOR

Most people have a large eating window each day, eat during more than 12 hours per day and have high intakes of protein.   Animal sources of protein will tend to activate mTOR strongly as they tend to contain more lucine, which is an activator of mTOR.   Bovine dairy, for instance, contains four times as much as human milk.  This means that most people will have mTOR activated throughout most of the day.  This is not congruent with health or longevity.  And so, for most people it is interesting to activate AMPK.

However, having AMPK constantly activated is also not healthy in the long run, especially because mTOR is anabolic and helps build muscle as well as other body parts.  It keeps stem cell populations healthy and allows for replacement of cells when needed.

You want AMPK activated most of the time, but also periods of mTOR activation.  What is optimal will vary from person to person and depend on their age and how damaged the body is.  Here is a suggestion for how to activate both,

  • Have a 20 hour fasting window twice a week and do vigorous exercise at the end of it,
  • Have at least a 14 hour fasting window daily, with some variations,
  • Do not take AMPK activating substances when you are starting to eat, have them as you start fasting

Senolytics

We can also take senolytics, substances that kill senescent cells, or senomorphics, substances that make the senescent cells transform back to their original form.

There are senolytic drugs but there are also natural substances that appear to have senolytic effects if taken in large enough doses.   

There are also senomorphic compounds like free radical scavangers and inhibitors of certain pathways (like the pro-inflammatory pathway NFkB, the lkB kinase, and Janus kinase pathway).  These do not kill the cells but reduce the toxic effects.  Some substances can actually be both senolytic and senomorphic, depending on which cells they affect.

Fisetin, for instance, is both a senolytic and a senomorphic, depending on which cells it affects.  It kills IR-induced senescent umbilical vein endothelial cells but is senomorphic on lung fibroblasts (IMR90).

Fisetin

Fisetin is a flavonoid found especially in strawberries (160 mg/kg).  In small quantities it is a neurotropic, antioxidant, anti-inflammatory, and anti-cancerous substance.  It can cross the blood-brain barrier, like quercetin.  It improves memory and lowers inflammation in the brain.  It can reduce allergic reactions and increase the production of the potent antioxidant glutathion.   

In recent studies it has shown to be a good candidate for a potent, natural senolytic.  In a study in mice and some human cells it was shown that  it killed 25-50% of the senescent cells, depending on the cell type.  This involved mice talking a high dose for five consecutive days.

Other doses were tested and it was found that when the dose is low there is no senolytic effect.  Interestingly this was done on relatively young mice and then on older mice.  It was effective in both cases.  As the younger mice that had been treated with fisetin got older they had comparably less senescent cells than untreated mice, indicating that there may be benefits to doing a senescent cell purge when younger, thus increasing healthspan.

Currently there are clinical trials going on in people.  The trials at the Mayo Clinic involve doses of 20 mg/kg for two consecutive days every 30 days.  From the trials we see some initial data showing improved gait speed and reduced inflammation markers.

Anecdotal Benefits of Large Dosis of Fisetin

There are persons in the biohacking community who have tried taking larger doses of fisetin for a few days.  These often involve around 20 mg/kg.  From them we can find that some experience relief from allergies, greater mental acuity, reduced inflammations, improvements in osteoarthritis, reduced herpes breakouts, and generally improved cognitive ability.  Others do not physically feel any difference.  However, these are only anecdotes and not scientific trials.

Some of the immediate and quickly passing side-effects that have been reported are light headaches, itching/burning/tingling sensations on the skin, lightheadedness, and a fever-like feeling.  Some people do not experience any side-effects.  Again this information is only anecdotal.

What about the senolytic properties of other natural substances?

Curcumin

Curcumin does seem to have some senolytic activity but it appears as though it may be best used in lower doses as an anti-inflammatory actor and an AMPK and sirtuin activator (and mTOR inhibitor).  At larger doses (some tests show 50 microM) it may be metabolically toxic and actually inhibit AMPK and sirtuins.

Because of its anti-inflammatory activity it will help prevent quick telomere shortening, which when present leads to senescence

EGCG from Green Tea

Epigallocatechin gallate (EGCG) is a polyphenol found in green tea.  It activates AMPK, inhibits mTOR and may lead to autophagic cell death.  It seems to be a senomorphic compound, at least in vitro, but not much is know about it being senolytic.

However, studies from large groups from Asia of regular green tea drinkers show that they tend to reduce their risk of a number of degenerative diseases by some 30%, and so it seems to be quite positive in some ways.

 

Resveratrol

Resveratrol is a flavonoid found in dark grapes.  It is an antioxidant and a potent sirtuin activator (see article on anti-ageing).  It can induce senescence in cancer cells but it is not know to be a senolytic.  Through its activity it can indirectly lead to reduced telomere dysfunction and thereby reduced senescence.

Quercetin

Quercetin is a flavonoid found in food, especially in capers.  It crosses the blood-brain barrier and can affect inflammation of the brain, herpes, etc.   It is a CD38 inhibitor and thereby may help prevent the age-related NAD decline.  It is a direct sirt1 activator and may indirectly help boost NAD levels and thus protect against senescence.  It also seems to have some senolytic properties and the most potent example may be when taken with the chemotherapeutic drug dasatinib.  On its own it is not clear how potent it can be as a senolytic, but probably not very potent.

Genistein

Genistein is an isoflavonoid found in plants, like alfalfa, peas, fava beans, soybean, etc.  It is an antioxidant, anti-inflammatory and anticancer agent. It seems to be a direct telomerase activator, and could thus retard replicative senescence.  Little is know about it as a senolytic but it is very interesting to note that it inibits  tyrosine kinase, thus it has the same target as dasatinib.  Dasatinib is a chemotherapy drug that taken together with quercetin was found to be a potent senolytic.  And so, the question is, how would quercetin work together with genistein?  Could that be a natural senolytic combination?

Berberine

Berberine is a substance (an isoquinoline alkaloid) present in the barberry and some other plants.  It is an antioxidant, antidiabetic, antiarryhythmic, and antihyperliidemic.

Berberien activates AMPK, inhibits nTOR and leads to autophagic cell death.  Interestingly enough, it seems to be as good at activating AMPK as the diabetes drug metformin.  This may be an interesting senolytic, but not enough is know about it.

Theaflavin

Extract from black tea leaves can be found in senolytic formulas.

Piperine

Piperine is found in black peppar and it tends to increase blood concentrations of certain flavanoids like curcumin, quercitine, and fisetinIt may in itself also have some anti-inflammatory properties as well as possibly anti-arthric ones.

Senolytic Cocktail

The easiest and currently perhaps most promising natural senolytic (apart from fasting) is fisetin, 20 mg/kg for up to five days in a row.  This means that a person weighing 60 kg would take 1200 mg of fisetin per day.

Perhaps in the future we will be able to create more potent senolytic cocktails based on studies. Today we can only speculate about what those might be.  These might perhaps involve the following items.

Fisetin has promise as a senolytic.  Perhaps taking 20 mg/kg could be an indication of what may work. To make it more potent one may take piperine.  This can increase the concentration in the blood by 30 times.  It may also be interesting to take it with some DHA oil (omega 3) to get a synergistic effect on the brain, as we know that fisetin gets into the brain.

Other possible additions having it with black tea, or taking theaflavons from black tea as a supplement, perhaps around 250mg.   Quercetin, some 1000mg,  may also of interest but the more one starts to mix the less we know about the interactions between the different substances.

Finally, a totally untried but in theory interesting mixture would be quercetin with genistein.

Combining senolytics with autophagy, meaning taking substances that activate AMPK or doing fasting seems like something that would further potentiate the results.  However one should not be taking NAD boosters at the same time.  It is good to first kill of senescent cells and only then go in with NAD boosters.

These possible senolytic cocktail components are all biohacker ideas and not scientific suggestions, based on human trials.

Reducing Senescent Cells - Action Plan

There are a number of things one can do to try to keep ones telomeres long and the sirtuins working properly to reduce senescence, as well as take action against the already present senescent cells.

All of this is in addition to a healthy lifestyle and diet.

 

  • Boost your NAD-levels (NAD-precursors (like NR), resveratrol, quercetin, fasting, exercise, heat/cold),
  • Take AMPK boosting supplements (or food)
  • Do 5 day fasts once or twice a year (or more often if needed),
  • Take fisetin for 5 days at 10 mg/kg a few times a year,
  • Consider Centella Asiatica or Astragalus supplements for telomere lengthening.

 

This is for educational purposes only.  Before you make any changes in your lifestyle and supplementation consult with your health practitioner because some of these actions may not be appropriate for your particular situation.

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REFERENCES

The references are present as yellow text links to the original articles throughout the text.

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