Are Pharmacological Approaches to Slow Aging in Fact Promising?
Today's open access review paper looks over a selection of what I would consider to be largely unpromising small molecules, each with evidence for their ability to slow aging, but very modestly and unreliably in most cases. Looking at the bigger picture, for much of the public it is still surprising to hear that the pace of aging can be adjusted via any form of therapy, so there is probably a role for simple, low-cost small molecule drugs in the process of education that leads to more serious efforts aimed at producing the means of human rejuvenation. Still, entirely too much effort is devoted towards small molecules that have inconsistent animal data (such as metformin), and also small effect sizes (such as metformin), and further are probably outpaced by the benefits of exercise - metformin again, but near all of the panoply of other calorie restriction mimetics that function via upregulation of cellular stress responses such as autophagy.
There are small molecules that are worth the effort, however. For example, senolytic therapies that selectively destroy senescent cells and produce rapid rejuvenation in animal models. This is far more interesting than the marginal slowing of aging produced by improved cell maintenance, not least because a single senolytic treatment results in lasting improvement as a result of the reduced burden of senescent cells. That said, there is at present a great deal more interest in the research and development community in producing small molecule drugs that alter metabolism to modestly slow aging, which have to be taken continuously over time, and which are unlikely to do better than lifestyle choices. A change in priorities is very much needed if we are to realize the promise of treating aging in our lifetimes.
Pharmacological Approaches to Decelerate Aging: A Promising Path
Aging is the principal risk factor for many illnesses such as cancer, cardiovascular disorders, and neurodegenerative diseases like Alzheimer's disease. Therefore, most elderly are being treated for a variety of chronic diseases and are suffering from side effects of the drugs. Only a 2% hindrance in the progression of aging, comparing with treatment of a disabling illness such as cancer would end up to a 10 million rise in healthier individuals and saving a large amount of budget. Hence, identifying smart therapeutic options that uphold the process of aging on one hand and simultaneously cease or decelerate the progression of age-related illnesses is of great significance.
The mTOR inhibitor rapamycin was first identified as an antifungal metabolite. The role of mTOR signaling pathway in longevity and extend of life span has been studied in numerous species. In general, inhibition of the mTOR pathway, either genetically or pharmacologically, has shown to increase lifespan in different species. The antiaging effects of rapamycin are exerted through various mechanisms, but the main route of action of rapamycin on the aging process is through inhibition of mTOR pathway. SIRT1 and AMPK occurs following inhibition of mTOR, so rapamycin can also be indirectly effective in the aging process by activating SIRT1 and AMPK following inhibition of the mTOR pathway. As known, mortality rate from infectious diseases is higher in older ages, which may be due to reduced immune function in old ages. One of the mechanisms by which the immune system is rejuvenated is the activation of autophagy. Inhibition of mTOR pathway can increase autophagy and therefore may be effective in increasing immune function during the aging process.
Resveratrol belongs to the polyphenol family exerting medical properties. The antiaging effect of resveratrol is exerted through several mechanisms. Resveratrol mimics the effects of caloric restriction (CR) and shows positive effects of CR in the aging process. It can have antiaging effects by inducing inhibitory effects on inflammation, improving mitochondrial function, suppressing oxidative stress, and regulating apoptosis. Another antiaging mechanism of resveratrol is through the activation of SIRT1. Activation of SIRT1 increases the antioxidant capacity of tissues and improves mitochondrial function.
Metformin is a biguanide and antidiabetic for the first-line treatment of type 2 diabetes. Metformin can lower plasma glucose levels and reduce the amount of glucose absorbed by the body and the amount of glucose produced by the liver. Metformin also enhances tissue sensitivity to insulin. Antiaging effects of metformin are governed by several mechanisms. In general, metformin activates AMPK and inhibits mTOR, downregulates IGF-1 signaling, reduces insulin levels, and inhibits electron transport chain (ETC) and mitochondrial complex 1.
Lithium is an alkali metal that is present in trace amounts in the body. The antiaging effect of lithium may be related to autophagy regulation, increasing telomere length, and enhancement of mitochondrial function in the brain. Inositol monophosphatase (IMPase) and glycogen synthase kinase-3 (GSK-3) contribute to the role of lithium in the regulation of autophagy.
Spermidine is a natural polyamine that is essential for cell proliferation and growth. Spermidine, as a polycation, binds to molecules such as DNA, RNA, and lipids, so it can play an important role in cellular functions. Spermidine affects autophagy, inflammation, DNA stability, transcription, and apoptosis. According to previous studies, spermidine can cause autophagy in multiple organs such as the liver, heart, and muscles. Spermidine induces autophagy by regulating the expression of autophagy-related genes such as Atg7, Atg15, and Atg11. Increased expression of elF5A and transcription factor EB (TFEB) by spermidine also induces autophagy.
Pterostilbene is an analogue of resveratrol from blueberries, which is obtained by both natural extraction and biosynthesis. Pterostilbene has anti-inflammatory, antioxidant, and antitumor effects. In a study investing the effect of pterostilbene on sepsis-induced liver injury, it was found that pterostilbene activates SIRT1, so it can also affect FOXO1, p53, and NF-κB. Pterostilbene also decreases the levels of inflammatory cytokines such as TNF-α and IL-6, decreases myeloperoxidase (MPO) activity, and increases Bcl-2 expression. Accordingly, pterostilbene can have anti-inflammatory and antiapoptotic effects.
Melatonin is a hormone in the pineal gland that affects many physiological functions. Melatonin secretion gradually decreases with aging. One of the antiaging mechanisms of melatonin is due to its antioxidant effects and reduction of oxidative stress, which leads to improved mitochondrial function. Melatonin has the ability to scavenge toxic free radicals and decrease reactive oxygen species (ROS) and can indirectly stimulate antioxidant enzymes such as GPx, glutathione reductase (GRd), and SOD. Melatonin also exerts its antiaging effects by increasing SIRT1 expression.
Acetylsalicylic acid or aspirin is obtained from the bark of the willow tree. Aspirin has a variety of medical uses. One of the main uses is to prevent secondary cardiovascular diseases. It also has analgesic and antitumor properties. The antiaging effects of aspirin on C. elegans, mice, and Drosophila melanogaster have been investigated. Lifespan increases when germ cell progenitors become ablated. One of the proposed antiaging mechanisms of aspirin is through its effect on the reduction of germline stem cells. Another proposed mechanism is improving intestinal barrier function by restricting the K63-linked ubiquitination and preventing intestinal immune deficiency.
Fisetin is a natural compound in the category of flavonoids. Fisetin can reduce age-related decline in brain function. This action can also be due to its antioxidant and anti-inflammatory effects. Fisetin can have a direct antioxidant effect and maintain mitochondrial function in the existence of oxidative stress and increase glutathione levels in cells. It has also anti-inflammatory effects against microglial cells by inhibition of 5-lipoxygenase and decreasing the production of lipid peroxides and inflammatory products. Fisetin can prevent neuroinflammation, neurodegeneration, and memory impairment by reducing oxidative stress. These functions are mediated by preventing the accumulation of ROS, inhibiting inflammatory cytokines, and regulating endogenous antioxidant mechanisms. Fisetin has senolytic effects as well by inhibiting the PI3K/AKT pathway. Downstream molecules of the mentioned pathway are involved in different parts of cellular processes by acting on the Akt/mTOR pathway that eventually leads to elimination of senescent cells. A study in mice found that taking fisetin reduces oxidative stress and inflammation and removes senescent cells; thus, tissue homeostasis is restored and lifespan is increased.
Slowing aging is in fact worse than doing nothing. Slowing aging will just make the world full of old people. Doing nothing will make them die sooner, meaning less old people. More old people is bad for the economics. The only solution is rejuvenation.
Beside the point J Weaver makes and which I feel to share I guess the drug approach is also criticized (in particular in the area of neurosciences) by Prof. Jean Hébert, now at the Albert Einstein College of Medicine, in some of his papers and 2020 book (Replacing Aging). To me the book has been the natural follow on Aubrey's and Rae's 15 years ago. Having observed (as an amateur though) the area since now 20+ years I start to feel there is too much hype and money and focus on the pharmacological approach rather that a sane complementarity ... I can understand industry and balance should also be brought by academia and public sector ... we might only go incremental and incidentally too slow for me which is secondary of course
I think that aging accelerators have a great future ahead of them. Plant breeding containing new types of aging accelerators. Current aging accelerators are no longer enough. People have been used to them for decades. Accelerators of aging have a positive effect because they reduce the incidence of diseases of old age in the population.
Reason, in your introduction you again cite senolytics as being very promisiing. Yet they have been around since ~2011 and I am unaware of a single positive effect from them in humans. Quite a few people around the globe have experimented with them, inclluding me (early 70s) and have seen no positive (or negative) changes. Are YOU aware of a single experimenter, who is old enough to have lots of senecent cells, that has seen a benefit from either Q+D or fisetin or PCC1 ? If so I am sure that many would love to hear a report on it as we are losing faith in this intially promising method.
@Dean: I know of a couple of older self-experimenters who liked the outcome of D+Q. That is also the therapy with encouraging human trial data, and a number of trials ongoing. What the whisper network of self-experimentation has to say is, of course, anecdata, and everything moves very slowly in the world of clinical trials. It is definitely the case that faster, few-hundred person D+Q trials should be run by responsible parties with philanthropic funding, to get decent data in front of physician networks more rapidly.