Category Archives: senescence

Low dose lithium reduces cellular senescence

A recent study shows that low-dose lithium may act as a senolytic.[ref] This has important implications in healthy aging – including preventing mortality from respiratory diseases, such as COVID, and neurodegenerative diseases like Alzheimer’s.

First, let me go into a little background information on lithium and then cellular senescence. Next, I’ll explain the new study on lithium as a senolytic and why this is so cool.

Lithium – naturally occurring mineral:

Lithium is perhaps best known for its use in batteries and as a drug for bipolar disorder.

As a naturally occurring mineral, lithium exists at varying levels in the soil and water throughout the world. According to estimates, people consume about 3mg of lithium a day from food and water, however, the amount varies a lot depending on where your food is grown and the source of your groundwater.

Epidemiological studies show that areas with higher levels of lithium in the groundwater have lower levels of suicide and assaults. Studies also correlate higher levels of lithium in water with lower levels of Alzheimer’s disease. (Read more about lithium and Alzheimer’s prevention.)

Lithium as a drug or supplement:

Lithium carbonate is about 19% elemental lithium. Thus a 300 mg dose prescribed for bipolar disorder would equate to about 57 mg of elemental lithium.

Microdoses of lithium carbonate used in clinical trials for Alzheimer’s disease are in the 300 μg to 30mg range. Elemental lithium would be around 57 μg to 5mg. Still a huge range, but in the ballpark of what a person likely consumes from food, depending on where the food is grown.

Several clinical trials now show that microdoses of lithium may prevent cognitive losses in AD.[ref][ref]

Supplemental lithium orotate is available in 5 mg – 20 mg doses. You can get it on Amazon or through health food stores.

Cellular senescence in aging:

Cellular senescence is a natural process that cells go through when they are at the end of their replicative life. When a cell can no longer replicate safely, it will send out signals for the immune system to destroy the cell. This is a process that occurs throughout life, but in older age, the number of senescent cells multiplies too rapidly for the immune system to keep up.

The signals that a senescent cell gives off are inflammatory cytokines. When all goes according to plan, the inflammatory cytokines cause a quick immune response. But in aging, the accumulated senescent cells give off a lot of inflammatory cytokines, increasing overall inflammation in the body. Uncleared senescent cells can cause harm to their neighboring cells through the signals that the cytokines give off.

A key issue in COVID-19 and other respiratory illnesses in the elderly is the hyperinflammatory response by the body. Excessive inflammatory cytokines lead to cell death and eventually to morality. One reason for the hyperinflammatory response in the elderly seems to be the high burden of inflammatory cytokine-producing senescent cells. (Read about cellular senescence in respiratory illnesses.)

Lithium as a senolytic:

The study on low-dose lithium as a senolytic shows that senescent cells treated with low concentrations of lithium decreased the inflammatory cytokines associated with senescence.[ref] The decrease in inflammatory markers included lower levels of IL-6.  Interleukin 6 (IL-6), an inflammatory cytokine, becomes elevated in COVID-19 in patients with severe disease.

The study results showed that the low-dose lithiums is acting via the same mechanism that high-dose amount act: prescription levels of lithium for bipolar disorder inhibits GSK3B activation.

Conclusion:

More research is needed to determine dosages and the mechanism of action of lithium as a senolytic. It is also not clear, to me at least, whether lithium is clearing out senescent cells, as a senolytic does, or if it is suppressing the cytokines from senescent cells.

In light of the recent FDA approval of a $56,000/year Alzheimer’s drug that doesn’t slow or reverse cognitive decline, I would love to see more trials on microdosing lithium for Alzheimer’s disease. The stark difference between a very cheap mineral supplement that does stop cognitive decline in Alzheimer’s patients vs. the horribly expensive drug that does not actually help…well, words fail me on why the government chooses via the FDA to pay for (via Medicare) a drug that is 1,000 times more expensive and yet less effective.

I would also love to see clinical trials on lithium as a senolytic in elderly people. Other senolytics, such as quercetin, fisetin, luteolin, and dasatinib, have shown efficacy in diseases related to senescence.[ref][ref] Lithium would be an even less expensive, readily available choice – if it is as effective as other senolytics.

 

 

Senolytics for COVID and other respiratory illnesses?

New research on COVID-19 shows the important role of cellular senescence in the high mortality rates in the elderly.

Elderly people are much more vulnerable to the flu, respiratory infections, and sepsis than middle-aged or younger adults. We all know that when grandma gets the flu in the nursing home, it is a serious matter. And we instinctively know that frailty is key – not all 75-year-olds are going to have the same vulnerability.

New research from the Mayo Clinic explains why the mortality risk from viral infections skyrockets in the elderly.

While the SARS-CoV-2 virus is new to the human population, COVID-19 deaths follow a similar pattern to other respiratory viruses that are commonly fatal in elderly or frail individuals: a weak initial immune response fails to kick the virus’s butt. But this is followed by a huge outpouring of an inflammatory response, and the heightened inflammatory cytokines end up causing cell death in the lungs and epithelial cells.[ref][ref]

It turns out that senescent cells play an active role in the hyperactive inflammatory response to respiratory pathogens.

Cellular senescence and hyper-inflammatory responses

Senescence describes cells that can no longer function and replicate. It is a response to DNA damage, wounds, oxidative stress, and other cellular insults.  Cellular senescence happens throughout life, and your immune system is responsible for clearing out the senescent cells. This is a really important way that the body prevents cancer and out-of-control cellular replication.

One cause of aging is that the number of senescent cells exceeds the capacity to clear them out. The scales tip towards more and more senescent cells with the immune system no longer able to keep up with clearing them out.

So why are senescent cells a problem in aging? 

Senescent cells give off inflammatory signals so that they can be cleaned up and cleared out by the immune system. Sometimes likened to ‘zombie cells’, the senescent cells not only don’t function, but they also impact surrounding cells due to the inflammatory signaling.

Thus, one problem with too many senescent cells in old age is they increase chronic inflammation – a sterile inflammatory response not due to a virus or pathogen. Cellular senescence can happen in all the tissues of the body, including immune system cells. Immunoscensence (too many senescent immune cells) is part of the reduced ability of an elderly person in fighting off pathogens.

But the senescent immune cells causing reduce immune response isn’t the whole story behind why the elderly are so much more likely to die from a viral or bacterial illness — especially in COVID-19.

Our immune system is pretty cool and able to recognize and fight off tons of different invaders through multiple lines of defense.

One way our immune systems recognize the bad guys is through pathogen-associated molecular patterns (PAMPs). These molecular markers reside on the surface of bacteria or viruses — and recognized by the immune system as always belonging to an invading bacteria or virus. It’s like a general ‘bad guy’ flag that the immune system attacks without knowing who exactly the bad guy is.

The lipopolysaccharides (LPSs) found on the cell membrane of gram-negative bacteria is an example of PAMPs. The immune system knows that LPS = bacteria, and it launches an immediate immune response without needing to know the specific bacteria.

COVID-19 and Pathogen-associated molecular patterns

Quick background:
The SARS-CoV-2 virus enters cells by attaching a spike protein to the ACE2 receptors.

Researchers at the SALK institute discovered that the spike protein alone causes the immune system to react -even without the accompanying SARS-CoV-2 virus invading cells.[ref]

Other research also shows that SARS-CoV-2 activates the PAMP response system.[ref] This isn’t new, nor unique to COVID. The pathogen pattern recognition receptors recognize the positive-sense RNA viruses in general, including other coronaviruses such as SARS and MERS.[ref][ref][ref]

Back to the new COVID-19 research:
This recent paper in Science by researchers at the Mayo Clinic shows that senescent cells significantly increase their inflammatory signals in response to activation of  PAMP. The senescent inflammatory signals are collectively known as SASP or senescence-associated secretory phenotype.

Specifically, the SARS-CoV-2 spike protein-1 activates the PAMP pathways and increases inflammatory signaling (SASP) from senescent cells. 

With senescent cells accumulating in the elderly added to an increase in inflammation when senescent cells are exposed to the spike protein, the hyper-inflammatory response seen in the elderly begins to make sense.

From the study: “certain inflammatory/SASP factors released by senescent human lung cell types, including IL-1α, IL-1β, IL-6, MCP-1, TNFα and MMP-1, are central to the pathological cytokine storm seen in some COVID-19 patients”.

In a nutshell, the spike protein identifies as a PAMP and causes senescent cells to pump out more and more inflammatory cytokines. These senescent cells produced cytokines then exacerbated the systemic inflammatory response. The hyper-inflammatory senescent cells then caused other surrounding cells to become senescent.[ref]

It seems to be a triple whammy in COVID – increased inflammation, more cellular senescence, and then an increased ability for the virus to enter the cells. For SARS-CoV-2, in addition to the ACE2 receptor, TMPRSS2 is necessary for cleaving the spike protein and required for the virus to enter a cell and replicate. Senescent cells upregulate TMPRSS2 in the surrounding healthy cells – thus increasing the ability of the virus to infect other cells.

From cell study to animal research:

The Mayo Clinic researchers went further than just showing that different senescent cell lines are activated by the spike protein.

The problem with elderly mortality isn’t limited just to SARS-CoV-2. The flu, pneumonia, common cold viruses, etc — all are much more likely to be deadly to someone who is elderly and frail.

Thus, the next part of the research study involved looking at the response in elderly mice to exposure to multiple microbes, including a beta-coronavirus, similar to SARS-CoV-2 but able to infect mice.

Lab mice live a sheltered life and aren’t exposed to all the bacteria and viruses to which mice in the wild or pet mice are constantly exposed. Pet store mice, especially, carry a lot of diseases.

When you expose old lab mice to mice from a pet store, they get sick and die from the various diseases carried by pet store mice. This is something that invariably happens within a couple of weeks of co-housing the mice. (Young lab mice don’t die from the exposure, just elderly lab mice.)

The researchers in the Science study found that the high number of senescent cells in the old mice was the key to mortality upon exposure to the high microbial load. The pre-existing senescent cells reacted to the pathogens, spreading high levels of inflammation.

But…it wasn’t all pathogens that caused this hyper-inflammation in the senescent cells. Through immunizing the old mice with the mouse version of the coronavirus, the researchers showed that the main driver of death in the old mice was actually the mouse beta-coronavirus.

Stopping the hyper-inflammatory response

In COVID-19 patients, a lot of emphasis has been on suppressing the body’s own immune response so that it doesn’t kill the patients.

In the elderly mice, the researchers were able to decrease mortality by half using senolytics, drugs that increase the clearance of senescent cells.

Giving senolytics after exposure to the mouse coronavirus cut the elderly lab mouse death rate from 100% dead within two weeks to about 50% mortality in two weeks.

The senolytic used in this part of the study was fisetin, a natural polyphenol compound, and it was given on days 3, 4, 11, and 12 after exposure to the viruses. This was followed by a second trial using quercetin plus Dasatinib, another senolytic cocktail used in research. The results with Dasatinib and quercetin were similar – 50% of the old mice surviving pathogen exposure compared to a 100% death rate in the control group.

Next step for the researchers: pretreating the elderly lab mice with senolytics before exposure to the coronavirus pathogen. The senolytic was given in two doses, several days before the exposure to the pathogens. The results showed pretreatment with senolytics reduced the mortality rate by about half, similar to giving the senolytics after exposure.

Prior research on cellular senescence and susceptibility to infection

While the Mayo Clinic study in Science is a fascinating look at how cellular senescence influences COVID-19 susceptibility, previous research shows this is not unique to the ‘novel’ coronavirus.

A higher burden of senescent cells is a key component to COPD and idiopathic pulmonary fibrosis (IPF).[ref] These two diseases are also linked to a significantly increased risk of pneumonia in older individuals.

In general, elderly people are at a 4-fold greater risk of pneumonia compared with non-elderly.

In older individuals, chronic low-grade inflammation, which includes elevated TNF-alpha and IL-6 levels, significantly increases the risk of pneumonia. Animal studies show that infusing young mice with TNF-alpha and IL-6 to the levels of old mice causes a similar susceptibility to pneumonia.[ref]

One big cause of chronically elevated TNF-alpha and IL-6 is the accumulation of cellular senescence and the inflammatory signals that the senescent cells give off (SASP).

Rapamycin is a drug that is being investigated for its impact on longevity and healthspan. Rapamycin is not a senolytic, per se, but instead suppresses the SASP signals from senescent cells. Animal studies show that rapamycin reduces mortality from pneumonia in aging animals via reducing lung damage from inflammatory cytokines, rather than working as an antibiotic.[ref]

In terms of COVID-19 research, cancer patients who have had chemotherapy have a higher rate of mortality than the general public.[ref] Certain chemotherapy agents induce a higher rate of cellular senescence.[ref]

Conclusion:

To me, the research on cellular senescence in COVID shows a clear picture of explaining a mechanism of hyper-inflammatory response. It makes sense of the high morbidity in frail people and in the comorbidities seen in those who are vulnerable to COVID-19.

The bigger picture here is that a high burden of cellular senescence adds to an inflammatory response. While inflammation is essential for healing wounds and fighting infection, an excessive inflammatory response will kill you. Thus, reducing the excess of senescent cells in aging may help to reverse chronic diseases as well as reduce mortality for pathogen infections. Clinical trials are underway on using senolytics in preventing diseases of aging.[ref]

If you want to know more about fisetin as a senolytic, check out this article on natural senolytics and this article specific to fisetin.

Some researchers hypothesize that microdoses of lithium act as a senolytic and may help with COVID.

Animal studies show an interesting link with NAC (n-acetyl cysteine) and reduced cellular senescence, but human trials are lacking there.[ref]

 

Targeting cellular senescence with natural compounds

Cellular senescence is a natural process that stops the reproduction of cells. While senescence happens throughout life, in aging, an accumulation of excess senescent cells seems to be at the heart of many age-related diseases.

What is cellular senescence?

Senescence is when a cell can no longer divide and has been damaged — but yet the cell remains in place and doesn’t go through cell death.

Senescence has dual outcomes:

  • On the one hand, stopping cellular reproduction in cells that have been damaged (DNA mutations, wounds, or tissue damage) is vital. This allows for wound repair and stops cancer from DNA mutations in the wrong genes. Stopping cancer is good!
  • On the other hand, senescent cells give off inflammatory and dangerous signals that increase chronic inflammation and negatively impact the health of surrounding cells. Chronic inflammation is bad.

Cellular senescence happens throughout your lifespan, but in aging, the rate of cellular senescence outpaces the ability of the body to eliminate the senescent cells.

Radiation, toxins, cellular stress, and cancerous mutations can all increase the number of senescent cells.

So what makes senescence so bad during aging? Why are damaged cells that just sit there and don’t grow – or die – bad? The answer is the dreadful SASP.

What is SASP?

One of the biggest issues with senescent cells is that they give off signals known as “Senescence Associated Secretory Phenotype’ or SASP.

If the senescent cell lingers longer than it should, these inflammatory signals cause damage to other surrounding cells and cause an overall increase in chronic inflammation in the body.

Naming names: SASP initially may consist of factors that are immunosuppressive such as TGF-β1 and TGF-β3, but as time goes on, the signals given off are more proinflammatory including TNF-alpha,  IL-1β, IL-6, and IL-8.  But not all senescent cells give off the same signaling molecules or export the same exosomes. Additionally, alterations in microRNAs, proteases, and an increase in reactive oxygen species are associated with SASP.[ref]

Estimations state that 30-70% of senescent cells develop a SASP signature.[ref]

While it is possible to target individual inflammatory cytokines, such as reducing TNF-alpha, the bigger picture when it comes to inflammation in aging is to clear out the senescent cells that are giving off the inflammatory signals.

What does increased senescence cause?

Here is a partial list of chronic diseases of aging that are caused, at least in part, by cellular senescence:[ref][ref]

  • frailty
  • macular degeneration
  • skin conditions such as psoriasis and non-healing wounds
  • COPD
  • dementias
  • atherosclerosis
  • chronic kidney disease
  • cancers
  • osteoarthritis
  • degenerative disc disease
  • idiopathic pulmonary fibrosis

Why is senescence such a problem in aging?

Younger people can keep senescence in balance, with their immune systems clearing out the cells in a timely fashion.

I don’t know that the question of why senescent cells accumulate so rapidly starting around age 60 has been fully answered yet in research.

Some researchers think that the body reaches a threshold at which it can no longer clear out enough senescent cells and accumulation starts to occur rather rapidly. Contributors to cellular senescence include DNA damage (toxins, radiation), cellular stress from reactive oxygen species, lipid toxicity, hypoxic stress, inflammation, and more.[ref]

The aging of the immune system is at least part of the picture in the inability to clear senescent cells. But part of the change to the immune system in aging is due to senescence. So it is a bit circular to point to the aging immune system as the cause of increased senescence, when the increase in senescent cells causes aging in the immune system.[ref]

Senolytics: targeting the senescent cells

Senolytics are drugs or natural compounds that decrease the burden of senescent cells. These molecules cause senescent cells to undergo apoptosis or cell death, while not killing healthy cells.

While we have known about cellular senescence since the 1960s, the science showing that these cells can be targeted and removed by certain molecules is less than a decade old.[ref]

One of the first senolytic drugs developed/discovered is dasatinib, which is a tyrosine kinase inhibitor used as a type of chemotherapy for leukemia. Specifically, dasatinib inhibits EFNB1 (ephrin B), a type of tyrosine kinase.

Of note here, not all tissue types have the same type of SASP, and some of the senolytics may better target specific tissue types than others.

It takes weeks to months for senescence cells to develop and to start giving off a SASP signature signal. So senolytics are often used only periodically instead of on a continual basis.[ref] The goal is to give your body’s natural ability to clear out senescent cells a periodic boost.

In most research studies, senolytics are used at high doses but just for a few days. This may then be repeated after a couple of months. Clinical trials are still ongoing to determine the more effective schedule and dosing.[ref]

Natural senolytics:

Until pharmaceutical senolytics go through clinical trials and are readily available for treating aging as a disease, many of us are left with relying on natural plant compounds that act as senolytics.

Heads-up:  Talk with your doctor before starting any supplements. Many natural substances can interact with pharmaceutical drugs, so check for interactions with any medications that you are on.

Quercetin:

One of the first natural substances investigated as a senolytic was quercetin. Many studies stack quercetin with dasatinib for a synergistic effect — attacking senescence in multiple ways.

Quercetin is a flavonoid found in apples, onions, and many other fruits and vegetables in small amounts.

A recent (small) clinical trial investigated the effect of a combination of dasatinib (100mg/day) and quercetin (1,000 mg/day) in patients with chronic diabetic kidney disease. The study participants received dasatinib + quercetin for three days. After 11 days post-treatment, biopsies of adipose and skin cells along with blood samples were examined. The results showed a decrease in senescent cells after 11 days in adipose tissue and blood, but no statistical effect in skin cells.[ref]

Another recent (small) clinical trial used 100 mg/day of dasatinib plus 1,250 mg/day of quercetin in patients with idiopathic pulmonary fibrosis. Again, the participants took the combination for three days and then were tested later for improvements. The one statically significant improvement was in physical function (walking speed and chair-stand times).[ref]

Animal studies on quercetin plus dasatinib show promise for heart disease, lung function, and osteoporosis. Three-day courses of the combined senolytics increased cardiac ejection fraction and decreased vascular calcification. Additionally, when given intermittently, the combination increased pulmonary function, and a reduction in pulmonary fibrosis occurred.[ref]

Interestingly, animal studies also show that quercetin plus dasatinib may reduce intestinal senescence as well as inflammation.[ref]

Of note with quercetin: it seems to be much more effective in conjunction with dasatinib, and there are questions surrounding the efficacy of quercetin alone as a senolytic.

Fisetin:

Fisetin is another naturally occurring flavone that works well as a senolytic. It acts as a selective BCL-x inhibitor.

Fisetin has shown in studies to selectively induce cell death in some types of senescent cells, but not all. For one, it doesn’t target senescent adipocytes (fat cells).[ref]

A study investigating ten natural compounds for their senolytic capacity found that fisetin was the top candidate as far as reducing the relative number of senolytic cells. Importantly, fisetin reduced senolytic cells without reducing healthy cells. Additionally, the study showed that either acute oral or chronic lower-dose fisetin reduced senescence and aging phenotype in mice.[ref]

Importantly, animal studies also show that fisetin extends lifespan while reducing age-related problems.[ref] Extending healthspan is the goal for senolytics, so it is good to see that a natural senolytic can have this benefit (in animals).

In the epithelial cells of the lungs, an animal study shows that fisetin inhibits senescence and reduced pulmonary fibrosis.[ref]

Another animal study showed that fisetin reduces atherosclerotic plaque and downregulates the expression of PCSK9 (important in cholesterol levels).[ref]

There is currently a clinical trial underway with the Mayo Clinic in older women using fisetin with a goal of reducing frailty and inflammation. The dosage being used is 20 mg/kg/day (oral) for two days a month with the trial lasting two months.[ref]

Piperlongumine:

Piperlongumine is a component of the fruit of the Piper longum (long pepper) plant.

There isn’t as much research on piperlongumine as the other natural compounds, but what is available is intriguing.

Several studies have shown that piperlongumine acts as a senolytic, selectively killing senescent cells. Interestingly, it works via targeting oxidative stress response proteins, which are elevated in senescent cells and cancer cells.[ref]

A 2018 mouse study showed that oral administration of piperlongumine increased neuronal plasticity and neurogenesis.[ref]

Piperlongumine may also act as an immunosuppressant for TH17. This may be beneficial for people with imbalanced T-cell differentiation, such as in autoimmune diseases, but of concern in other situations. Of note, the study showed the effect only when thiols were not present.[ref] Additionally piperlongumine may also act as an anti-clotting agent.[ref]

Curcumin:

Curcumin, a component of the spice turmeric, is a readily available supplement that has some senolytic properties.

A study looking at the senolytic properties of curcumin and one of its metabolites, o-Vanillin, shows that it can clear senescent cells from intervertebral discs.[ref]

Animal studies show that curcumin, at higher doses, can act as a senolytic – in certain tissues.[ref]

Note that curcumin can act as a blood thinner.

Phloretin:

Phloretin (Dihydronaringenin) is a flavonoid that has been investigated for its anti-cancer possibilities.[ref] It is a polyphenol found in apples and is metabolized to produced phloridzin.  

Phloretin has shown in several cell and animal studies to have senolytic effects.[ref]

This seems to be a compound with potential, but with a lot more research needed.

EGCG:

Epigallocatechin gallate, EGCG, is a bioactive compound found in green tea.

While EGCG is not a senolytic, a cell study shows the EGCG increases SIRT3 activity, which may delay cellular senescence. The study used senescent adipocytes (fat cells).[ref]

Combining natural compounds as senolytics:

A recent cell study showed that the combination of resveratrol, curcumin (bioCurcumin), and liposomal β-caryophyllene significantly reduced several components of senescent cells including reducing L-1β, IL-6, and TNF-α expression levels and increasing SIRT1.[ref]

In different tissue types, senescent cells may need to be targeted with different compounds. Some senescent cell types can be targeted via BCL-2, which is also what quercetin acts upon. Other cell types are better targeted via PI3 kinase delta or BCL-xL. Thus, a combination of different senolytic compounds may give a better overall response.

 

Side effects from natural senolytics:

Gastrointestinal side effects are possible from higher doses of many of the natural senolytics.[ref]

Quercetin and fisetin both inhibit COMT and could lead to irritability, anger, or anxiety in people with COMT genetic variants. Maybe.

Anecdotally, fisetin at higher doses may cause a flu-like feeling.

Seriously, check for interactions if you are on any medications. High doses of supplements can interact with many medications.

Fisetin reduces blood sugar levels in animals. If you tend to have problems with hypoglycemia, you may want to be cautious with fisetin.[ref]

Where to find natural senolytics:

The amounts of these natural flavonoids used in the trials, whether human or animal, are much higher than what you could get from eating fruits and vegetables.

Quercetin is readily available at most health food stores and online via Amazon. Read the reviews and pick out your favorite brand of capsules or as a powder. Just as a warning – quercetin is a yellow powder that stains, so use caution if trying to create your own capsules with it.

Research shows that eating a meal that contains fat along with the quercetin supplement can increase bioavailability.[ref] Transdermal absorption of quercetin (mixed with oil/fat) is possible.[ref] Again, quercetin is yellow, and it stains the skin with a nice jaundice-like hue.

Dasatinib is a prescription medication in the US. It may also be available as a research chemical from some online peptide stores, but the question of quality and purity is one that you should investigate thoroughly before going down that path.

Fisetin is available as a supplement from several manufacturers either in capsules or as a powder. High-dose fisetin is used as a senolytic for just a few days at a time. Your better bet for higher doses may be to use the powdered form of fisetin. Note that the Mayo clinical trial (no results yet) is using a dose of 20 mg/kg/day for two days in older women.

While not commercially available (that I can find), a liposomal formulation of fisetin may be many times more bioavailable.[ref] Other studies also point to fisetin encapsulated in fat being more bioavailable.[ref] While no human studies seem to be available on this, it may be that fisetin is more absorbable if taken along with fat.

Fisetin can also be applied topically and has been studied in animals for reversing photoaging.[ref][ref]

Piperlongumine seems to only be available as a research chemical. Long peppers are available as a food, but I don’t know that it would be possible to consume enough to make a difference as a senolytic. Apparently, long pepper is quite spicy.

Phloretin is available as a very expensive skincare product. I have no idea how well it works for skincare. Phloridzin, the metabolite of phloretin, is available in apple polyphenol supplements, but at low dosages (5% of supplement weight).