Anti-Aging Therapies
A brief introduction to existing aging theories, anti-aging therapies, and self-related motivations.
The Truth
There’s no such thing as healthy aging. Aging is a disease and in fact when it occurs earlier than expected we classify it as such (Progeria). In the 1960s the NIH separated disease from aging by calling diseases such as Alzheimer’s, Parkinson’s, Cardiovascular diseases as ‘aging-related diseases’. It wasn’t until recently in ICD-11 that aging was classified as a severe risk factor, but even so it’s still not classified as a disease when really it is. Aging ‘related’ diseases are not aging-related, they’re aging-caused. Even now, there’s been this ‘pro-aging trance’ as Dr. De Grey puts it where we’ve accepted aging and let it ravage our minds and bodies because we fear there is nothing we can do to stop it.
How much do you think a 70 or 80 or 90 year old would give for an hour as a 25 year old? To have less pain, more mobility, and to have the freedom to explore? In this blog I hope to help shake you out of this trance as aging is one of the greatest problems of our generation and like any great problem we can strive and hope for a solution.
Hallmarks of Aging
Any theory of aging would need to address the damage described by Aubrey De Grey and Michael in “Ending Aging” as well as the other hallmarks of aging mentioned by Dr. David Sinclair and Dr. Michael Fosset. De Grey approaches anti-aging therapies as an engineer, hypothesizing that like a car if we fix each part when it breaks down the car will be able to run forever. He created SENS (Strategies for Engineered Negligible Senescence) and proposed attacking the damage associated with aging by first categorizing all damage and then creating targeted solutions.
Expanded hallmarks of aging in addition to the ones above include
- Genomic instability.
- Telomere length shortening.
- Dysfunction in proteostatsis
- Mitochondrial dysfunction.
- Reduced intracellular communication
- Epigenetic instability.
- ‘Zombie’ senescent cells (cells that don’t divide and don’t want to die. Quercetin triggers apoptosis in these cells).
There are many more dysfunctions associated with aging but the above highlights many of the significant ones.
Theories of Aging
Telomere Theory of Aging
The two main theories of aging that I’ve read extensively are the telomerase theory of aging and the information theory of aging. The telomerase theory of aging claims that age is caused by the progressive shortening of telomeres which changes gene expression and then impacts metabolism. Without getting too technical, our DNA is stored in the nucleus of a cell as chromatin, a string of DNA wrapped around histones and open to be transcribed into mRNA. When a cell needs to divide all of the DNA in the nucleus has to be copied but due to the mechanism of DNA replication there’s a bit of a problem:
Before the DNA is copied, DNA polymerase needs to ‘find’ where to land and begin. This is the job of the RNA primase, which tells DNA polyemerase where to land on the DNA and begin replicating. However, DNA polymerase doesn’t replace the RNA primer, so once it’s removed there’s regions of DNA that wasn’t copied, called ‘overhangs’. That means that every time a cell divides a little bit of the DNA is lost!
Telomerase solves this problem by adding repeated DNA sequences to the end of the DNA protecting the DNA for each subsequent replication.
But the activity of telomerase is not enough. As we age our telomeres progressively get shorter, and leads to something called the Hayflick limit: the max number of divisions a cell can have before it stops entirely because the telomeres are too short. The telomerase theory of aging hypothesizes that aging is the result of reduced cellular vitality as new cells cannot be created and this old cell becomes senescent. Any additional divisions of near-senescent cells reduces DNA information in the daugther cells destroying genetic information when the telomere cap is gone.
For the longest time, I was a big proponent of this theory but there were a few questions that befuddled me: if telomeres are the cause of aging then any therapy that extends telomeres in cells should halt aging completely. Transcription factors like TA-65, Astragalosides (like Cycloastragenol), seem to increase the lengths of telomeres in mammals but is not sufficient to halt aging, suggesting that telomere shortening is a symptom of aging but not the cause.
Which leads to another idea…
Information Theory of Aging
The primordial survival circuit:
Dr. David Sinclair in his book ‘Lifespan’ describes the below survival circuit as a model for the survival circuits that we have all inherited. In essence, our bodies have more advanced circuits that are designed to protect against how damage and stress; i.e. when damaged drop everything and fix it.
Dr. Sinclair’s Information Theory of Aging suggests that aging is due to epigenetic noise where this noise causes an exponential loss in epigentic information that overloads survival networks and causes cell instability in a positive feedback loop. We observe that the movement of epigentic factors causes cells to become ex-differentiated which and worse at their original function.
As a refresher, DNA can be thought of as the digital recipe listing the ingredients of our life while the epigenome can be thought of as the analog codebook describing the amount (10 of gene A, 0 of gene B, .5 of gene C, …). The epigenome consists of the histones and chemicals that wrap and sit on top of the DNA. These chemicals involve any factor that regulates the expression of certain genes on the DNA. The epigenome is responsible for the differentiation of all our cells; a muscle cell and a skin cell have the same DNA but a different epigentic fingerprint that creates a unique gene expression for both cells.
The difficultly with the epigentic information sitting on top of the DNA, i.e. the unique pattern of transcription factors or chemicals sitting on top of each cell, is that once it’s lost how can we recover it? Is it even possible to recover it? It’s like having all the ingredients but having no idea of the amounts: the wrong amounts create a dysfunctional cell. DNA is easier as it’s digital but returning the billions of chemicals to their original place on top of the DNA is astronomically difficult if the original structure is lost.
Cue the exciting parts:
We’ve known for a while that cloning a mammal from an old cell is possible, i.e. if I take the cell of an old frog place it into an embryo after removing the nucleus a tadpole will grow. What this implies is that even if we loose a lot of epigenetic information in our cells over time there exists an original epigentic template that tells the cell how to reset the epigenetic structure to its youthful state. This is proof that we have a backup of the ingredient amounts for each gene, a backup of the original epigenetic structure, somewhere and can tell an old cell how to become a young cell again. Dr. Sinclair equates this to Claude Shannon’s error correcting information channel.
Young cells also have the ability to repair significant damage, unlike old cells. For a long time neuronal damage was thought to be irreparable if it occurred after the newborn period. Yuancheng Lu proved in what is one of the most fantastic experiments I have ever read that this is no longer the case.
Using three of the four Yamanaka factors ((Oct3/4, Sox2, Klf4) not (c-Myc )) a group of protein transcription factors that induce pluripotent stem cells) Lu created a reprogramming virus that he injected into these mice. Lu crushed the optic nerve in mice causing all the axons to retreat away from the crush site. Once the reprogramming genes were turned on using doxycycline however, something amazing happened: the axons grew back. In the control this just didn’t happen as we know from countless other. The implication is that by activating the three Yamanaka factors the epigenomic structure on top of the DNA can be recovered, reset the cells to their youthful state, and restore their intended function.
The Anti-Aging Hype and why I’m hooked
The current anti-aging therapies and drugs seem to fit into the information theory of aging framework and impact our mammalian survival circuits. However a healthy dose of understanding and skepticism is needed before diving head first into taking random drugs as too much of a good thing could do the opposite. The pathways below are a bit more involved but having a high-level understanding should put into context many of the anti-aging drugs we see and hear about.
Longevity genes (extensions of the survival circuit)
Sirtuins
Sirtuins are a protein responsible for cellular homeostasis and cellular repair. Sirtuins are linked to NAD+which is a critical coenzyme to our cells.
Increasing eNAD+ produces more sirtuins which in turn helps communication with the nucleus, mitochondria, and inter-tissue communication particularly with the hypothalamus. As we age however nicotinamide phosphoribosyltransferase (NAMPT) production is impacted reducing sirtuin production and causing us to age. Drugs like NMN (ADD LINK) increase eNAD+ which in turn boost sirtuin production.
TOR
TOR nutrient-responsive kinases is another protein that exists in an aging related circuit. Inhibiting TOR increased the lifespan in some model organisms. TOR activation contributes to the aging process. When the amounts of nutrients, growth factors, and energy availability are sufficient, TOR switches off stress resistance and autophagy pathways and switches on cellular growth pathways and protein synthesis. The analogy is driving your car at 100mph and noticing the engine is on fire but still reviving anyway. TOR’s job is to keep the engine running: create proteins, grow the cell. Left on the car wont pull over to check the engine even if the light is blinking. Hence, inhibition of mTOR can prolong lifespan but continued inhibition is just as bad. In our car analogy this is like leaving the car sitting in the garage for to long: the battery dies and the engine rusts. TOR is a quasi-promoter of aging as it does not fix aging but instead slows it. In rodent models, long-term mTOR inhibition can cause issues (cataracts, testicular degeneration) but the effects are reversed with immediate cessation for a couple of weeks.
Drugs like Rapamycin inhibits both mTORC2 and mTORC1 (antiaging effect only in mTORC1) while Metformin inhibits mTORC1 and decreases translation. Both drugs require a prescription if you can get one.
AMPK (AMP-activated protein kinase)
AMPK is another compound that when produced inhibits TOR, activates Sirtuins and is also activated by compounds like Metformin and Resveratrol (a chemical found in red wine). AMPK activation increases autophagy, aptosis of senscent cells, and protects agains oxidative stress. AMPK responsiveness decreases with age.
The above pathways are the most actively researched as far as I can tell. Most of the compounds or anti-aging habits (caloric restriction) that are being promoted tend to impact one or multiple of these. Observing these circuits together illustrates that while these compounds will not end aging they maybe at the very least be able to slow it down.
The Regime
I’m 24 years old and already I’ve begun to notice the subtle signs of aging: more wrinkles, takes longer to recover from a bump or scratch, subtle joint pain. I’ve seen the effects on my parents & have seen it cause the death of my grandparents. My hope is to inspire our generation to recognize that aging can be treated as Dr. David Sinclair, Dr. Aubrey de Grey, and Dr. Micheal Fosset have done for me. Perhaps anti-aging treatments will be created in my generation; perhaps not. Regardless ending aging is possible.
Below is the set of drugs I take (they’re affiliate links to the drugs that I buy, buying helps me continue writing articles but no worries if you get it elsewhere). Note I’m not a doctor, this is just what I choose to take in order to hopefully slow the aging process in myself.
May you all live long and live young!
- NMN, 500 mg, 5 days / week
- Resveratrol, 600mg, 5 days / week
- Cycloastragenol, 5mg, 5 days / week
- TA-65, 2 mg, 3 days / week
- Quercetin, 1000mg, 5 days / week
- Tumeric, 500 mg, 5 days / week
- Cinnamon extract, 1000 mg, 5 days / week
- Wim Hof method, Cold showers.
Below is the set of drugs I’d like to take but they require a prescription to be affordable.
- Metaformin
- Rapamycin
References
[1] Sirtuins increase aging in mammals
[2] TOR pathway and link to longevity
[3] AMPK pathway and link to longevity
[4] AMPK image
Burkewitz K., Weir H.J.M., Mair W.B. (2016) AMPK as a Pro-longevity Target. In: Cordero M., Viollet B. (eds) AMP-activated Protein Kinase. Experientia Supplementum, vol 107. Springer, Cham. https://doi.org/10.1007/978-3-319-43589-3_10
[5] Lifespan by Dr. David Sinclair
[6] Ending Aging by Dr. Aubrey de Grey and Dr. Micheal Rae
[7] Telomerase Revolution by Dr. Michael Fossel
[8] Reprogramming damaged neurons in the optic nerve by Yuancheng Lu
