Known interventions and pathways that influence aging

Highlights:

• The most well-studied pathways that influence aging are the mTOR pathway, the IGF-1 pathway, the AMPK pathway and the NF-KB pathway
• Sirtuins are proteins that are involved in aging processes and longevity
  

Introduction

For many decades, it has been well known that lifespan is malleable through different interventions across multiple organisms. Already in the 1930s, it was discovered at Clive McKay's lab that mice fed a low-calorie diet lived longer. This initial finding gave rise to the concept that one could extend lifespan with scientific methods. Until these discoveries were made, aging was believed to be something that could not change at all, and subsequently, aging research was treated as purely descriptive and not something where the impact could be made.

Biogerontology

Evidence for the plasticity of lifespan created legitimacy to biogerontology, which previously was seen as an area for charlatans. For decades calorie restriction remained the only known method to extend lifespan in organisms. However, in the 1980s, genetics that could affect lifespan were discovered. The first among them was AGE-1 in C. elegans discovered by Klass and Johnson in 1982 (1, 2). While aging is a very complex multifactorial phenomenon, it is nonetheless understood to some extent. In this list overview, we look at some of the well-known pathways that have experimental evidence behind them to influence lifespan.  

The mTOR pathway

This pathway (abbreviation for Mechanistic Target of Rapamycin) was discovered by David Sabatini Ph.D. It regulates cell growth as well as metabolism. The discovery of mTOR was made from realizing it was the target that the antifungal agent rapamycin acted upon. While rapamycin was discovered already in the 1970s, it remained largely forgotten, and its breakthrough as an anti-aging drug came in the late 2000s when it was shown to extend life in mice (3). mTOR consists of two complexes that mediate different effects in the body called mTORC1 and mTORC2; mTORC1 is mainly autophagy (cell recycling), cell growth, and proliferation mTORC2 has effects on lipid metabolism, cytoskeleton, and cell survival.

mTOR inhibition is the most well-established researched pharmacological way to extend life; rapamycin robustly and consistently extends the lifespan of mice by 10-20%. It should be noted that this life extension is on top of the average lifespan of generally healthy wild-type mice. In mice with accelerated aging, it extends life even further. This is in contrast to many substances that improve health and extend life in the prematurely aged research models but that do not affect the lifespan of already aged mice. While rapamycin extends life, it also has side effects since it suppresses the immune system and is therefore used in large doses for organ transplant patients to prevent rejection. That being said, it is thought that low-dose rapamycin would be safer and a potential intervention to extend life in humans. This has also led to an industry where multiple biotech companies are working on improving age-related disease through mTOR inhibitors. 

The IGF-1 pathway

It has been found that IGF-1 inhibition extends life across organisms (4). Apart from the AGE-1 mutation in the nematode C. elegans, several other pathways have been discovered that extend life, such as DAF-2, which is a famous discovery by Cynthia Kenyon back in 1993. Mutations in DAF-2 were found to extend lifespan dramatically by up to 800% compared to the normal nematodes. In humans the condition where IGF-1 levels are dramatically reduced due to genetic mutations is called Laron syndrome. This syndrome is common in certain families living in Ecuador with ancestry from Israel and results in a dramatically shortened stature (around 140 cm) and extreme protection against cancer. The lifespan data in people suffering from Laron dwarfism is still unclear but believed to be longer than average. Apart from the social disadvantages of being around 140 cm tall, the people with Laron Syndrome are generally healthy. IGF-inhibition can be induced by medications such as pegvisomant and octreotide. These drugs are normally used to treat pituitary dysfunctions such as acromegaly. It is unknown if giving these drugs to healthy adult people would extend their lives and reduce their risk for cancers like a genetic deficiency.

The AMPK pathway 

AMPK is an abbreviation for AMP-activated kinase, and it is a pathway regulating cellular energy uptake and metabolism. The diabetes drug metformin is by far the most well-studied drug activating AMPK. However, the compound AICAR is generally used to activate this pathway in lab settings; it cannot be used in a human due to the quantities required due to low oral bioavailability. 

Exercise also affects AMPK, and it is believed that some of the beneficial effects of being physically active are mediated by AMPK activation (5). Metformin has been out on the market for several decades as a first-line treatment for diabetes type 2, and there is data showing a reduction in the rates of cancer and heart disease among people taking this drug. Because of this, a large-scale clinical trial on metformin has been set up in the US called the TAME trial (Targeting aging with metformin). This trial aims to demonstrate that metformin is not only good for diabetes but can be used to generally reduce the burden of age-related disease in the elderly population. 

The NF-KB pathway

This pathway is central in inflammation which goes up with age. There is an excess of inflammation across the aging body due to both an aging immune system and reactions to the tissue damage that aging causes, such as senescent cells. Many drugs that affect inflammation inhibit NF-KB and generate a health benefit in the elderly even if not restoring the aged tissue since the inflammation itself is bad and accelerates aging further (6). Things that can lower inflammation with increasing age are a healthy lifestyle, statins, fish oil, and aspirin.

The most well-known efficient drugs that inhibit NF-KB are corticosteroids; however, they have severe side effects and are not suitable to improve health in the elderly. Further evidence of the importance of inflammation in aging has been observed in anti-inflammatory drug trials such as the Cantos trial, the Colchicine trial, and longitudinal follow-up of people taking the anti-asthmatic drug Montelukast. Finally, some results on common statins, such as rosuvastatin, have indicated that the positive effects of statins on cardiovascular disease may be due to lowering inflammation rather than reducing cholesterol. 

The mitochondrial drugs - PGC1-Alpha/NAD+

Many drugs can affect mitochondrial function and possibly extend life and improve health (7). Urolithin A is a PGC-1 alpha activator that promotes mitochondrial biogenesis, which could mean more mitochondria in older humans (8). SS-31 (Elamipretide) increases ATP synthesis and is hypothesized to have a beneficial effect on the elderly, although clinical trials have not shown solid evidence.

Nicotinamide Riboside and Nicotinamide Mononucleotide that does increase the amount of NAD+ will improve mitochondrial function. There are many studies on mice showing cardiovascular benefits and improved exercise capacity. 

Sirtuins and other pathways

Sirtuins are proteins that are involved in stress responses. The data on sirtuin activation as being beneficial is generally more mixed than the other targets listed above. Drugs that activate sirtuins are called Sirtuin-activating compounds (STACs). Others include natural plant chemicals like quercetin, which also function as sirtuin activators (9).

Summary

When it comes to interventions extending life, mTOR inhibition is the most effective and consistent method where data is plentiful across multiple organisms. However, combinatorial therapies would produce the most significant effect on aging, although studies are lacking. The different damages of aging overlap and create a feedback loop that makes multiple interventions necessary to produce the maximum effect on a specific condition. 

References

1. Berkel, C., Cacan, E. A collective analysis of lifespan-extending compounds in diverse model organisms, and of species whose lifespan can be extended the most by the application of compounds. Biogerontology (2021). 
2. Uno, M., Nishida, E. Lifespan-regulating genes in C. elegans. npj Aging Mech Dis 2, 16010 (2016).
3. Papadopoli D, Boulay K, Kazak L, et al. mTOR as a central regulator of lifespan and aging. F1000Res. 2019;8:F1000 Faculty Rev-998. Published 2019 Jul 2. doi:10.12688/f1000research.17196.1
4. Bartke A, Chandrashekar V, Dominici F, Turyn D, Kinney B, Steger R, Kopchick JJ. Insulin-like growth factor 1 (IGF-1) and aging: controversies and new insights. Biogerontology. 2003;4(1):1-8. doi: 10.1023/a:1022448532248. PMID: 12652183.
5. Salminen A, Kaarniranta K. AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network. Ageing Res Rev. 2012 Apr;11(2):230-41. doi: 10.1016/j.arr.2011.12.005. Epub 2011 Dec 15. PMID: 22186033.
6. Tilstra JS, Clauson CL, Niedernhofer LJ, Robbins PD. NF-κB in Aging and Disease. Aging Dis. 2011;2(6):449-465.
7. Sun N, Youle RJ, Finkel T. The Mitochondrial Basis of Aging. Mol Cell. 2016;61(5):654-666. doi:10.1016/j.molcel.2016.01.028
8. Andreux, P.A., Blanco-Bose, W., Ryu, D. et al. The mitophagy activator urolithin A is safe and induces a molecular signature of improved mitochondrial and cellular health in humans. Nat Metab 1, 595–603 (2019)
9. Dai H, Sinclair DA, Ellis JL, Steegborn C. Sirtuin activators and inhibitors: Promises, achievements, and challenges. Pharmacol Ther. 2018;188:140-154. doi:10.1016/j.pharmthera.2018.03.004

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