Virtually everybody has taken acetaminophen (also known as paracetamol) from time to time; probably a lot of it over the years. It is of course the key ingredient in the over-the-counter pain-killer Tylenol®, is widely sold as an inexpensive over-the-counter analgesic and is included in a very large number of proprietary OTC pain formulations. Could something so familiar and so mundane as acetaminophen have anti-aging properties? That is the story I explore here.
This is the first blog entry inspired by what I came across in the last few days at the American Aging Association’s 39th annual meeting in Portland Oregon. Wandering through the poster presentations I came across one entitled Acetaminophen improves Protein Translational Signaling in Aged Skeletal Muscle prepared by a team including Miazong Wu and Hua Liu from Marshall University. Scanning the poster quickly I came across an assertion that grabbed my attention, and that is that “Acetaminophen improves mTOR-related signaling in aged skeletal muscles.” Further, in a rat study “Compared to 26 and 27 month old F344BN rats the expression of the mTOR complex proteins raptor and GbetaL and the phosphorylation of the negative regulator tuberin/TSC2 (Thr1462) were reduced in the soleus muscles of very aged animals (33 months old).” I thought “improves” the signaling meant reduces it, but I was wrong.
Background on mTOR
I will come back to this research shortly but first want to say why I so-quickly became excited when I scanned the poster. Inhibition of mTOR signaling is one of extremely few interventions known that can extend lives across a variety of species including mammals. I have mentioned mTOR frequently in this blog. See the earlier blog post Longevity genes, mTOR and lifespan. I repeat “Mammalian target of rapamycin (mTOR) is a protein encoded in humans by the FRAP1 gene. As the name suggests, mTOR is targeted by the immunosuppressive drug rapamycin, a drug used clinically to treat graft rejection and restenosis and being tested as a treatment for autoimmune diseases.“ Inhibiting the expression of mTOR produces all kinds of health effects in experimental animals. The blog entry Viva mTOR! Caveat mTOR! tells how feeding rapamycin to mice late in life inhibits mTOR expression and extends their lives, so rapamycin is being considered as a longevity drug for humans. I also describes potential hazards of taking it. The blog entry More mTOR links to aging theories looks at the involvement of the mTOR pathway in the hypoxic response biochemical pathway involved in aging and in the stem cell supply chain theory of aging. Finally, I added a candidate theory of aging to my treatise Increasing mTOR signalling.
A bottom-line conclusion of all this background is that if we could find a safe way to inhibit the expression of mTOR we might well live longer – 14% for males and 8% for females both average and maximum if we are like mice(ref). So the possibility of being able to extend our lives using something so simple and relatively safe as acetaminophen came across as very exciting to me. Unfortunately, looking a bit more carefully this possibility seems unlikely. “Improving” mTOR signaling as described in the poster meant increasing it, not reducing it. So, I am afraid that taking acetaminophen is likely to work at cross-purposes and on the whole be a negative intervention.
Getting back to the current presentation at the AAAS meeting, the poster presentation appeared to document the case for acetaminophen “improving” the expression of TOR in mouse tissues and having rejuvenating effects on mouse muscle tissues fairly well, but that latest work still remains unpublished even in abstract form. However, some of the same the authors published a paper in 2009 describing earlier stages of their work Aging-Associated Dysfunction of Akt/Protein Kinase B: S-Nitrosylation and Acetaminophen Intervention. “Here we report a novel dysfunction of Akt in aging muscle, which may relate to S-nitrosylation and can be prevented by acetaminophen intervention. – Principal Findings — Compared to 6- and 27-month rats, the phosphorylation of Akt (Ser473 and Thr308) was higher in soleus muscles of very aged rats (33-months). Paradoxically, these increases in Akt phosphorylation were associated with diminished mammalian target of rapamycin (mTOR) phosphorylation, along with decreased levels of insulin receptor beta (IR-β), phosphoinositide 3-kinase (PI3K), phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and phosphorylation of phosphoinositide-dependent kinase-1 (PDK1) (Ser241). In vitro Akt kinase measurements and ex vivo muscle incubation experiments demonstrated age-related impairments of Akt kinase activity, which were associated with increases in Akt S-nitrosylation and inducible nitric oxide synthase (iNOS). Impairments in Akt function occurred parallel to increases in myocyte apoptosis and decreases in myocyte size and the expression of myosin and actin. These age-related disorders were attenuated by treating aged (27-month) animals with acetaminophen (30 mg/kg body weight/day) for 6-months “Our results show that aging skeletal muscle exhibits impaired Akt kinase activity and that acetaminophen-induced improvements in Akt signaling are associated with increases in myocyte size and the expression of myosin and actin, along with decreases in muscle apoptosis.”
A number of protein analyses studies described in the 2009 paper demonstrated “Dysfunction of Akt in the very aged muscle can be corrected by acetaminophen,” “Akt dysfunction is associated with increases in iNOS and Akt S-nitrosylation,” “Akt hyper-phosphorylation is associated with a loss of PTEN protein,” “Akt dysfunction is associated with decreases of muscle fiber cross-sectional area,” and “Akt dysregulation is associated with increases in myocyte apoptosis.”
Of relevance to our focus on mTOR, the 2009 paper reported “Compared to 6- and 27-month rats, the phosphorylation of Akt (Ser473 and Thr308) was higher in soleus muscles of very aged rats (33-months). Paradoxically, these increases in Akt phosphorylation were associated with diminished mammalian target of rapamycin (mTOR) phosphorylation, — The abundance of phosphorylated mTOR (pmTOR) (Ser2448) and mTOR total protein in the very aged soleus were lower than that in the adult animals (−86.3% and −86.8%, respectively; P<0.05.” In other words there was an age-related decline in mTOR expression in these muscle cells that accompanied accelerated expression of certain Akt proteins and loss of functionality. Moreover “chronic acetaminophen treatment restored the amount of phosphorylated and total mTOR to a level equivalent to that seen in 6- and 27-month old animals (P>0.05).”
The ability of acetaminophen to correct age-related problems in aged muscle was reported on in the above-mentioned 2009 paper, but the role of mTOR in the process is only clarified in the current 2010 yet-unpublished poster presentation. I quote only selectively from what was on the poster or the printed abstract for it. “Here we hypothysize that age-related impairments in Akt/mTOR function are associated with reduced translational signaling and that these age-associated alterations, if present, can be attenuated by acetaminophen treatment.” — “Compared to 6 and 27 month old F344BN rats, the expression of the mTOR-complex proteins raptor and GbetaL and the phosphorylation of negative regulator tuberin/TSC2 (Thr1462) were reduced in the soleus muscle of very aged animals (33months old). These changes in Akt/mTOR pathway signaling proteins were in turn associated with decreased phosphorylation.” “ — Age-associated alterations in the Akt/mTOR pathway signaling and in the phosphorylation of the stress-responsive eIF2alpha protein were attenuated by chronic acetaminophen treatment –Conclusion: Aging is associated with impairments in the regulation of proteins thought to be important in controlling mRNA translation and acetaminophen may be useful for the treatment of age-related muscle atrophy by reducing oxidative stress.” (Whoops, in this condensed presentation I not quite sure where the last conclusion related to oxidative stress comes from.)
The 2009 publication Impaired overload-induced hypertrophy in Obese Zucker rat slow-twitch skeletal muscle provides independent confirmation that inadequate mTOR expression may be responsible for stress or age-related atrophy in the soleus muscle. “Taken together, these data suggest that IR or other related co-morbidities may impair the ability of the soleus to activate mTOR signaling and undergo load-induced muscle hypertrophy.” If you are further interested in the molecular signaling pathways that affect muscle atrophy and hypertrophy, you can start with Akt signalling through GSK-3β, mTOR and Foxo1 is involved in human skeletal muscle hypertrophy and atrophy, and then work your way through the citations.
So the situation appears to be:
– The study described in the poster and its antecedent publication suggest that age-related muscle atrophy is likely to be due to (or at least associated with) age-related decline in Akt/mTOR signaling and that this atrophy can be at least partially offset by increasing Akt/mTOR signaling using acetaminophen. In aged muscle cells a strategy for longevity of capability is increasing mTOR signaling.
– Other studies covered in previous blog entries suggest that median and maximal lifespan of organisms including mice and possibly people can be increased by inhibiting mTOR signaling.
The paradox is one I have possibly encountered before. As I recall, there are many who argue that HGH administration can increase muscle strength, vitality and several indicators of youth but there is also evidence that it does not extend and possibly shortens lifespans(ref)(ref).
Both the poster and the earlier report record feeding the mice with acetaminophen (30 mg/kg body weight/day) for 6-months. For a 150 pound human being this is equivalent to a 2,045mg daily dose. Taking large chronic doses of acetaminophen is potentially risky. “While generally safe for use at recommended doses (1,000 mg per single dose and up to 4,000 mg per day for adults, up to 2,000 mg per day if drinking alcohol[2]), acute overdoses of paracetamol can cause potentially fatal liver damage and, in rare individuals, a normal dose can do the same; the risk is heightened by alcohol consumption. Paracetamol toxicity is the foremost cause of acute liver failure in the Western world, and accounts for most drug overdoses in the United States, the United Kingdom, Australia and New Zealand(ref).[3][4][5][6] ”
I have put the giant bottle of acetaminophen tablets from Costco back under the bathroom sink.
I find myself strongly over it and love learning on this topic,and melted it a bit leaving resin on the bottom of the part,2