Hi all,
A few months ago, I wrote and submitted an ITP proposal– still awaiting back whether or not it has been accepted.
In the meantime, I’m looking forward to writing up some more applications by the end of this year. Attached below is a list of drugs I’m considering writing proposals for; I’d appreciate other suggestions if any come to mind.
Thanks in advance!
ITP Drugs of Interest - Single drug.pdf (53.5 KB)
Fantastic to hear - Great to see the effort! We need more people doing this.
I looked at the ITP submission examples and realized it takes a lot of time and research to pull together a good submission, which I didn’t have at the moment - but for someone who has the time, I think its a great use of time.
Submission examples and info here: Feb. 28th Cutoff For NIA ITP Aging Drug Submissions - Ideas for New Testing?
What do you think about this?:
Based on that study:
Why?
Rapamycin and Rifampicin alone increased lifespan in C Elegans by 20%, in combination they increased lifespan of C Elegans by 30-50% (they tried it a few times). It also worked in Drosophila better than Rapamycin alone
What dose?: Rapamycin: 44 ppm, Rifampicin: 20 ppm
Rapamycin + Rifampicin + Allantoin gave even more lifespan extension but I would focus on this 2 compound combination first
What dose?: Glycine 10 000 ppm, NAC: 10 000 ppm
Why? It increased lifespan in Drosophila by 45%
What dose?: Rapamycin: 44 ppm, lithium: 25 ppm, Trametinib: I don’t know*
*There are some studies from Linda Partridge where mice dose where it extended lifespan can be found
Rapamycin + Acarbose + NAC + glycine
Why? Because we should focus on testing if we can improve Rapamycin and NAC + glycine has good results in human studies
Different rapalogs (Everolimus, etc)
Thanks for the info! Going to add some of these to the sheet.
Could you give me the citations for all of these life extension figures? That first paper doesn’t mention life extension figures unless I missed it.
Rapamycin+Acarbose+NAC+Glycine would be very interesting. If they could get an additional 10-20% lifespan VS Rapamycin and Acarbose alone it would be game changing.
My ultimate dream combo would be Rapamycin+Acarbose+NAC+Glycine+Carnosine+Astaxanthin+EGCG+Glucosamine+Lithium That would cover a lot of different cellular aging pathways.
For 1. Rapamycin + Rifampicin:
The largest effects obtained for the triple combinations
RAP+RIF+ALLAN (89% MLSP extension) and RIF+PSORA+
ALLAN (96% MLSP extension) are comparable to canonical aging mutations such as daf-2 (up to 100% MLSP extension)
and age-1 (between 50% and 65% MLSP extension)
https://www.cell.com/developmental-cell/pdfExtended/S1534-5807(18)30699-3
There are also survival curves there
RIF+PSORA+ALLAN gave even more lifespan extension in C Elegans, but it gave only something like 20% in Drosophila - where Rapamycin + Rifampicin + Allantoin gave about 60% in Drosophila
Also Rapamycin + Rifampicin worked in Drosophila almost as good as Rapamycin + Rifampicin + Allantoin
For nr 3:
We show that the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib, the mTOR complex 1 (mTORC1) inhibitor rapamycin, and the glycogen synthase kinase-3 (GSK-3) inhibitor lithium act additively to increase longevity in Drosophila . Remarkably, the triple drug combination increased lifespan by 48%.
in c. elegans / nematode worms…
Interesting list. Some comments:
PPAR-\gamma is already being probed with two glitazone class drugs, what additional benefits are you proposing?
Do useful klotho enhancing agents actually exist?
Deprenyl is, IIRC, a \sigma_1 agonist as well as MAO_B inhibitor. So probably better to just test that.
Might it be better to consider other PDE inhibitors, possibly even caffeine or other methylxanthines? Or even a PDE5i with better kinetics than sildenafil.
feeding mouse with Royal Jelly,
Queen bees that are fed royal jelly typically live longer than worker bees. Royal jelly is a special type of secretion produced by worker bees that is fed exclusively to queen bees during their development. This special diet of royal jelly is believed to be responsible for the longer lifespan and greater fertility of queen bees compared to worker bees even tough they share the same genetic code.
On average, a queen bee can live for two to three years, although some may live for up to five years. In contrast, worker bees typically live for just a few weeks
Have there been any lifespan studies on royal jelly in other organisms - nematodes, flies, etc.?
Does anybody know if they ever tested bovine lactoferrin?
Here is the list of all the compounds tested:
yes, Lifespan-extending effects of royal jelly and its related substances on the nematode Caenorhabditis elegans
https://pubmed.ncbi.nlm.nih.gov/21858156/
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0023527
Interesting theory. Would love to see some literature of royal jelly being tested in more organisms (might be an ant specific pathway that makes it so effective). Otherwise it might be a difficult pitch for a proposal.
Thanks for the input! Great questions. Will get back to you on these.
Three papers about Taurine. Taurine is a supplement that I wish the ITP program could test. Taurine has many interesting effects. It has distinct effects on mitochondrial health and on cardiovascular health.
The Role of Taurine in Mitochondria Health: More Than Just an Antioxidant - PMC (nih.gov)
“Taurine is a naturally occurring sulfur-containing amino acid that is found abundantly in excitatory tissues, such as the heart, brain, retina and skeletal muscles. Taurine was first isolated in the 1800s, but not much was known about this molecule until the 1990s. In 1985, taurine was first approved as the treatment among heart failure patients in Japan. Accumulating studies have shown that taurine supplementation also protects against pathologies associated with mitochondrial defects, such as aging, mitochondrial diseases, metabolic syndrome, cancer, cardiovascular diseases and neurological disorders. In this review, we will provide a general overview on the mitochondria biology and the consequence of mitochondrial defects in pathologies. Then, we will discuss the antioxidant action of taurine, particularly in relation to the maintenance of mitochondria function. We will also describe several reported studies on the current use of taurine supplementation in several mitochondria-associated pathologies in humans.”
“Taurine is a sulfur-containing amino acid and known as semi-essential in mammals and is produced chiefly by the liver and kidney. It presents in different organs, including retina, brain, heart and placenta and demonstrates extensive physiological activities within the body. In the several disease models, it attenuates inflammation- and oxidative stress-mediated injuries. Taurine also modulates ER stress, Ca2+ homeostasis and neuronal activity at the molecular level as part of its broader roles. Different cellular processes such as energy metabolism, gene expression, osmosis and quality control of protein are regulated by taurine. In addition, taurine displays potential ameliorating effects against different neurological disorders such as neurodegenerative diseases, stroke, epilepsy and diabetic neuropathy and protects against injuries and toxicities of the nervous system.”
https://www.biomolther.org/journal/view.html?volume=26&number=3&spage=225&year=2018
“Taurine is an abundant, β-amino acid with diverse cytoprotective activity. In some species, taurine is an essential nutrient but in man it is considered a semi-essential nutrient, although cells lacking taurine show major pathology. These findings have spurred interest in the potential use of taurine as a therapeutic agent. The discovery that taurine is an effective therapy against congestive heart failure led to the study of taurine as a therapeutic agent against other disease conditions. Today, taurine has been approved for the treatment of congestive heart failure in Japan and shows promise in the treatment of several other diseases. The present review summarizes studies supporting a role of taurine in the treatment of diseases of muscle, the central nervous system, and the cardiovascular system. In addition, taurine is extremely effective in the treatment of the mitochondrial disease, mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), and offers a new approach for the treatment of metabolic diseases, such as diabetes, and inflammatory diseases, such as arthritis.”
The intracellular concentration of taurine is commonly 5–50 mM and the plasma concentration of taurine is approximately 100 μM. When taurine is supplemented, the plasma taurine content usually reaches its peak within 1 h to 2.5 h of taurine intake. In an analysis on the pharmacokinetics of oral taurine supplementation (4 g) in healthy adults. These individuals, who had fasted overnight, showed a baseline taurine content in a range of 30 μmol to 60 μmol. Then, 1.5 h after taurine intake, the plasma taurine content increased to approximately 500 μmol. Plasma taurine content subsequently decreased to baseline level 6.5 h after taurine intake.
i guess one issues with having a large combination is that we won’t know what’s contributing to any benefit that is observed. And perhaps some of the elements counteract each other? But I guess each combination of the molecules at different doses could potentially be tested on simple models like worms, etc. (e.g. with the technology at Ora Biomedicals)
I’d be interested in Rapamycin + Acarbose + Luteolin + ezetimibe
Acarbose for inhibiting alpha-glucosidase and alpha-amylase
Luteolin for inhibiting fructokinase
Ezetimibe for inhibiting the absorption of cholesterol
I believe these 3 have minimal side effects so one need not worry too much about the ideal dose
I understand that issue, but I think ITP should think outside the box once in a while. If you combine several compounds you could find surprising synergy effects that is unexpected. They won’t know before they try it.
One of 5 trials they do, should be a moon shot if you ask me.