Just some AI Fun With Hallmarks of Aging
Please don't take this too seriously. It's just an experiment.
The 12 Hallmarks of Aging are biological processes that contribute to aging and associated decline in function. Initially, there were 9 hallmarks (proposed in 2013), but recent updates have expanded the list to 12. These hallmarks are grouped into primary, antagonistic, and integrative categories. Whether you subscribe to 9 or 12 hallmarks of aging, these lists represent a growing consensus about what aging is, and how interventions might impact aging. Ideally, an antiaging drug or treatment would show improvements to all 12 of these measurements.
Since an increasing number of small molecules has emerged to prolong lifespan and health in experimental animals, from yeast to vertebrates, an obvious question is whether some combination of these drugs could target multiple Hallmarks causing an additive effect to increase lifespan even further.[2] This has been shown to be true in some cases (like Rapamycin + Metformin) but not in others.
Rapamycin is a common drug in such tests, and is known to target and help with “Deregulated Nutrient Sensing” by inhibiting the mTOR signaling pathway. But it is also known that it does not have high impacts on some of the Hallmarks.
And while Rapamycin primarily impacts deregulated nutrient sensing, it also impacts other Hallmarks, including loss of proteostasis, mitochondrial dysfunction, cellular senescence, and altered intercellular communication.
Deregulated Nutrient Sensing
Rapamycin directly targets the mTOR pathway, which is a key regulator of nutrient sensing and cellular growth. Inhibition of mTOR mimics caloric restriction, promoting longevity by reducing protein synthesis, improving stress resistance, and enhancing cellular maintenance.
Loss of Proteostasis
mTOR inhibition by rapamycin enhances autophagy, the process by which cells degrade and recycle damaged proteins and organelles. This helps to maintain proteostasis, counteracting the accumulation of misfolded and aggregated proteins, which is a hallmark of aging.
Mitochondrial Dysfunction
Rapamycin can improve mitochondrial function through its role in stimulating autophagy (mitophagy) and reducing energy expenditure associated with excessive cellular growth. This process helps maintain mitochondrial quality and function.
Cellular Senescence
Rapamycin has been shown to reduce cellular senescence by limiting the pro-inflammatory secretory phenotype (SASP) associated with senescent cells. This can reduce chronic inflammation and tissue dysfunction in aging.
Even though Rapamycin can impact several Hallmarks, it only mildly increases the lifespan of lab animals. Also we know that adding other chemicals can have an additive effect and increase lifespan further. And these additive effects are now a focus for longevity researchers.
One speculation is that several, or all of these Hallmarks would have to be moderately or strongly altered at the same time to have significant lifespan effects. So how could that be achieved?
1. Rapamycin + Metformin
Rapamycin: Inhibits the mTOR pathway, enhancing autophagy, reducing cellular senescence, and mimicking caloric restriction.
Metformin: Activates AMPK, improves mitochondrial function, reduces inflammation, and enhances nutrient sensing.
Targeted Hallmarks:
Deregulated nutrient sensing
Mitochondrial dysfunction
Loss of proteostasis
Cellular senescence
Rationale: Rapamycin and metformin both mimic caloric restriction, but through different mechanisms (mTOR inhibition vs. AMPK activation). Together, they may amplify the benefits of caloric restriction and enhance metabolic health.
Impacts: according to a 2016 study conducted by the National Institute on Aging Interventions Testing Program, a combination of metformin and rapamycin increases maximal lifespan by 23 percent in lab animals. (this is greater than either drug individually)[1]
2. NAD+ Boosters + Rapamycin
NAD+ Boosters: Compounds like nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN) restore NAD+ levels, improving mitochondrial function, DNA repair, and cellular metabolism.
Rapamycin: Enhances autophagy, improves proteostasis, and reduces senescence.
Targeted Hallmarks:
Mitochondrial dysfunction
Genomic instability
Loss of proteostasis
Deregulated nutrient sensing
Rationale: NAD+ boosters improve mitochondrial health and energy metabolism, while rapamycin enhances cellular maintenance processes. Together, they address energy deficits and cellular stress.
Exercises for the Reader
I don’t believe that AIs are ready to figure out the fountain of youth for us, but they are getting better. So I thought this would be a fun experiment.
If you want to experiment with this a bit, I would suggest prompting an AI with something like this:
“What combination of drugs (like rapamycin,metformin, spermindine, senolytics), or methods (like 'heterochronic parabiosis', 'caloric restriction', 'senolytic treatment', 'stem cell therapy'), or genes (assuming a gene therapy existed that could inhibit or enhance that gene), or other lifespan extending treatments, might be able to have an additive effect on lifespan by targeting the 12 hallmarks of aging (Genomic Instability, Telomere Attrition, Epigenetic Alterations, Loss of Proteostasis, Deregulated Nutrient Sensing, Mitochondrial Dysfunction, Cellular Senescence, Stem Cell Exhaustion, Altered Intercellular Communication, Chronic Inflammation, Dysbiosis, Macronutrient Sensing) . Can you map some of these combinations to the Hallmarks they might affect in a chart with combinations in rows, and hallmarks as columns.”
Depending on which AI you chose, you may get a chart like this:
Charting these drugs and which Hallmarks they target might be educational, for speculating about what mixture might give a synergistic effect. For example, this chart suggests that combining a TERT and FOX03A gene therapy with Rapamycin seems like an interesting combo.
Here is another attempt:
What combination of drugs (like rapamycin,metformin, spermindine, berberine,cycloastragenol, senolytics), or methods (like 'heterochronic parabiosis', 'caloric restriction', 'senolytic treatment', 'stem cell therapy'), or genes like TERT, Klotho, FOXO,OCT4, SOX2, KLF4, SIRT6, p53, IGF-1 (assuming a gene therapy existed that could inhibit or enhance that gene), or other lifespan extending treatments, might be able to have an additive effect on lifespan by targeting the 12 hallmarks of aging (Genomic Instability, Telomere Attrition, Epigenetic Alterations, Loss of Proteostasis, Deregulated Nutrient Sensing, Mitochondrial Dysfunction, Cellular Senescence, Stem Cell Exhaustion, Altered Intercellular Communication, Chronic Inflammation, Dysbiosis, Macronutrient Sensing) . Can you map some of these combinations to the Hallmarks they might affect in a chart with combinations in rows, and hallmarks as columns. which gives this:
We have read that Rapamycin + Metformin has an additive effect, resulting in a 26% lifespan increase for mice, so it is not surprising that this combo affects multiple Hallmarks in the chart above. Of course, charting Rapamycin+metformin helps reduce cellular senescence, but some drugs like fisetin or azithromycin actually kill senescent cells, so they might potentiate the effect on Hallmark 7 (Cellular Senescence), though you can’t see that from this chart. So maybe dividing Cellular senescence into senotherapeutics vs senolytics might be helpful?
Here is another attempt. But these types of charts will quickly make you realize that this method does not tell you how MUCH each factor may help. Even if some combo hit all Hallmarks, it doesn’t really ensure a big lifespan increase! A mild effect on all 12 Hallmarks doesn’t really make much difference in lifespan, when the experiment is done.
What combination of drugs (like rapamycin,metformin, spermindine, berberine,cycloastragenol, senolytics), or simple methods (like 'caloric restriction', 'senolytic treatment', 'stem cell therapy'), might be able to have an additive effect on lifespan by targeting the 12 hallmarks of aging (Genomic Instability, Telomere Attrition, Epigenetic Alterations, Loss of Proteostasis, Deregulated Nutrient Sensing, Mitochondrial Dysfunction, Cellular Senescence, Stem Cell Exhaustion, Altered Intercellular Communication, Chronic Inflammation, Dysbiosis, Macronutrient Sensing) . Make combinations that impact as many Hallmarks as possible. Can you map some of these combinations to the Hallmarks they might affect in a chart with combinations in rows, and hallmarks as columns. Assume the experimental animal does normal basic health techniques and lifestyle for longevity like exercise, avoiding obesity, balanced nutritional diet, and no poisons like cigarettes are used,so do not list any of those.
This last chart makes it appear that a combination of metformin, rapamycin, spermidine, senolytics, and caloric restriction (CR) could have a good effect. Of course CR is difficult for most people do perform long term, so it isn’t an ideal combo.
One thing I noticed is that different AIs give very different answers. Gemini is very optimistic, suggesting that many drugs or treatments hit most Hallmarks either directly or indirectly, thus making it appear that most combination treatments should increase lifespan in some additive way, but we know that is not true.
Again
One more try, showed something interesting:
What combination of drugs (like rapamycin,metformin, spermindine,berberine,cycloastragenol, acarbose, trehalose, phenformin, senolytics like Azithromycin /fisetin/quercetin), or other drugs seen in research as having potent antiaging benefits, or simple methods (like 'caloric restriction', 'Fecal Microbiota Transplantation', 'senolytic treatment', might be able to have an additive effect on lifespan by targeting the 12 hallmarks of aging (Genomic Instability, Telomere Attrition, Epigenetic Alterations, Loss of Proteostasis, Deregulated Nutrient Sensing, Mitochondrial Dysfunction, Cellular Senescence, Stem Cell Exhaustion, Altered Intercellular Communication, Chronic Inflammation, Dysbiosis, Macronutrient Sensing) . Some drugs like rapamycin and metformin have been shown to have additive effects, perhaps due to affecting different Hallmarks or biochemical signaling pathways.
Make combinations that do not duplicate effects, but impact as many Hallmarks of Aging as possible, to a
medium to high impact.
Can you map some of these combinations to the Hallmarks they might affect in a chart with combinations in rows, and hallmarks as columns. Focus on drugs shown to have additive effects in research. Assume the experimental animal does normal basic health techniques and lifestyle for longevity like exercise, avoiding obesity, balanced nutritional diet, and no poisons like cigarettes are used,so do not list any of those lifestyle effects in the combinations. Label each combination as being expected to be low med or high in impact. Only list those with an overall medium to high expected effect.
#10 combo shows a good coverage of Hallmarks
For another useful bit of homework, you might go to scholar.google.com and search for combinations like this, to find other useful articles:
combination rapamycin metformin senolytic
So what is next?
So far this has been a bit frustrating. The AIs will use chemicals that I suggest, but don’t really seem to be coming up with a list of better antiaging chemicals, or anything unexpected. I would like some combo that hits all 12 Hallmarks, and hits them hard.
Can an AI solve this for me? This time I asked the question backwards:
What Hallmarks would not be targeted well with a combination of Cycloastragenol + Metformin + AKG + rapamycin + Sulforaphane + fisetin + berberine + AICAR + NAD precursors (NMN,NR) + aspirin + trehalose + intermittent fasting +MitoQ +SkQ1 + melatonin + creatine + astragalus root + taurine + dehydroepiandrosterone (DHEA) + N-acetyl-L-cysteine (NAC) + multivitamins + betaine + excercise + fastingIn this case, many Hallmarks were addressed, but it is still not clear if they were hit hard enough to actually makes some difference. Here is what it said:
Let me analyze this systematically by comparing the listed interventions against the Hallmarks of Aging:
Genomic Instability
Telomere Attrition
Epigenetic Alterations
Loss of Proteostasis
Deregulated Nutrient Sensing
Mitochondrial Dysfunction
Cellular Senescence
Stem Cell Exhaustion
Altered Intercellular Communication
Your comprehensive stack appears to address most hallmarks but may have relative gaps in:
Stem Cell Exhaustion
While some compounds like cycloastragenol and exercise have mild effects on stem cell function, this hallmark could potentially benefit from additional targeted interventions.
Altered Intercellular Communication
Though some components like rapamycin and fisetin influence inflammatory signaling, this hallmark might benefit from additional interventions targeting specific intercellular signaling pathways.
Genomic Instability
While NAC, sulforaphane, and some other components provide DNA protection, this fundamental hallmark might benefit from additional DNA repair pathway support.
This is interesting for a few reasons:
-no gene therapy seems needed, in theory, to get some effects on many of the Hallmarks of Aging.
- there are small molecules to target most of the Hallmarks to one degree or the other
- AIs are getting smarter in Biology
-AIs normally warn you about safety, but it didn’t put in any warnings about weird herbs or drug-drug interactions…
Safety note
Firstly, be skeptical of anything that an AI says. Secondly, any speculations like this need to be tested in the lab. And thirdly, none of this should be assumed to be safe unless it has been tested on humans.
If you did this excercise, you will notice the AIs output a lot of caveats and warnings. And rightly so. Some of these chemicals are prescription drugs, and have side effects. Some have interactions with other medicines.
Herbs mentioned here have multiple components inside, and dose can vary with growing conditions. And we all know that the difference between a medicine and a poison sometimes is the dose (think digitalis and Foxglove). [3]
Removing senescent cells might improve the lifespan of lab rats, but in humans could have negative effects since these cells help in kidneys, immune response, etc. Likely Rapamycin could reduce immune response in some cases. So as always, what works in rats may not work, or be safe in humans.