Various Ageing Stubs

Autophagy

Autophagy is the process by which cells (or cellular components) eat themselves under conditions of nutrient deprivation (AKA fasting)

https://podcastnotes.org/2019/07/11/autophagy/

Alzheimer’s

The vaccine research involved a new field in immunology called endobody vaccines.

Endobodies: Most vaccines prepare our body’s immune system to fight off so-called exogenous disease, such as measles or flu, caused by bacteria or viruses entering our blood. Endobody vaccines, on the other hand, prime our immune system to deal with malfunctioning internal parts of the body that it would otherwise ignore.

United Neuroscience.

(earlier work) epitopes – fragments of proteins, five to six amino acids long, that play a critical role in the body’s defence against external diseases.
The human immune system relies on a collection of cells and proteins to identify, neutralise and destroy invaders. The body’s first two lines of defence are inflammation and the so-called neutrophil cells. Inflammation is caused by damaged cells releasing chemicals that cause blood vessels in the area to leak, swelling the tissue with fluid and isolating the foreign substance. Neutrophils are white blood cells that then ingest invaders and break down their protein chains. The next wave of defence – white cells called microphages – “eat” the neutrophils, extracting fractions of the invading proteins and attaching them to the surface of their cell wall. These fractions are the so-called epitopes.

After the body has defeated the invasion, it stores a blueprint of the successful B cells and T cells. This makes it much faster at fighting another bout of the same disease, swamping the threat before it has time to spread. Most immunisation against disease involves mimicking an infection by injecting an inactivated or attenuated form of the invader to trigger the immune system – should an infection occur, the immune system will then respond before the person becomes ill.

She created synthetic versions of the tiny chains of amino acids that trigger the production of antibodies. In the case of her Alzheimer’s vaccine, this allowed her to develop a mechanism that triggers antibodies to the Alzheimer’s protein in the blood. These then attract T cells that attack any protein with an antibody attached.

Chang Yi’s vaccines use molecules that are so small, they don’t trigger inflammation.

Since then the disease has risen to become the leading cause of death for women and the second leading cause for men in the UK: combating Alzheimer’s would be a dramatic medical achievement. 

Over the last 15 years, UK mortality statistics have shown a steady decline in deaths from heart disease, strokes and most major cancers – for men and women. Over the same period the death rate from dementia – of which Alzheimer’s is the most common cause – has doubled: in part because lifespans have increased, and the effects of the disease increase with age. In the UK, there are currently 850,000 people living with dementia, and 500,000 – perhaps as many as two-thirds – have Alzheimer’s. 

A total of five drugs are available to relieve symptoms, but they cannot slow or stop the progression of the disease. There is no known cure. Following diagnosis, life expectancy is typically between three and nine years.

Although we don’t know much about Alzheimer’s, researchers believe its effects are caused by two rogue proteins, beta-amyloid and tau – high amounts of both are found in the brains of people with Alzheimer’s. Beta-amyloid was discovered in 1984, with tau identified two years later.

For reasons that are unclear, damaged beta-amyloid can misfold into a “sticky” form that clumps together in a tangle of fibres – called plaques – that accumulate around nerve cells and disrupt cell communication, metabolism and repair. 

Both proteins may cause brain cell damage, although researchers aren’t sure if high levels of beta-amyloid and tau cause Alzheimer’s or are symptoms of the condition. 

Chang Yi’s vaccine – UB-311 ( UB-312, the Parkinson’s vaccine )– couples a synthetic imitation of a common disease with a specific sequence of amino acids that are present only in the damaged beta-amyloid protein, and absent in the healthy form. This provokes an antibody response, clearing the tangled proteins away without provoking potentially damaging inflammation.

In January 2019, the company announced the first results from a phase IIa clinical trial in 42 human patients. “We were able to generate some antibodies in all patients, which is unusual for vaccines,” Chang Yi explains with a huge grin. “We’re talking about almost a 100 per cent response rate. So far, we have seen an improvement in three out of three measurements of cognitive performance for patients with mild Alzheimer’s disease.”

to immuno-sculpt people against chronic illness and chronic ageing with vaccines as prolific as vaccines for infectious diseases.

https://www.wired.co.uk/article/alzheimers-vaccine-united-neuroscience

Links June-July 2019

June-July 2019 – not all links, will be more consistent in the future.

https://link.springer.com/referenceworkentry/10.1007%2F978-3-319-69892-2_395-1

Big library, found originally via Longevity Activism post/page on there

https://www.sciencedaily.com/releases/2019/06/190617164701.htm

Antioxidant puts up fight, but loses battle against protein linked to Alzheimer’s disease

http://arep.med.harvard.edu/gmc/protect.html

Genetic alleles and protection they offer

https://www.ldeming.com/longevityfaq#explanation

Good beginners post, Laura Deming

https://onlinelibrary.wiley.com/doi/full/10.1111/j.1474-9726.2009.00533.x

Mouse studies, only 1/5 (at least in this paper) showed longer lives through caloric restriction, some shorter

https://podcastnotes.org/2019/01/30/sinclair/

Interview with David Sinclair, notes from the podcast with many interesting links

https://podcastnotes.org/2019/01/17/attia-5/

Interview with Peter Attia, notes from the podcast with many interesting links

https://podcastnotes.org/2018/08/14/mtor/

Interview with David Sabatini, notes from the podcast with many interesting links, mtor discussion, Rapamycin

https://podcastnotes.org/2019/07/11/autophagy/

Podcast, Mike Mutzle, autophagy

https://www.nytimes.com/2019/07/15/opinion/future-billionaires.html

Paul Krugman, NYT, billionaires shouldn’t live forever, opinion piece (imagined future)

https://www.youtube.com/watch?v=Yfd041nvaIo&t=0s

Engineering Better Medicines from our Own Cells | Krystyn Van Vliet | TEDxMIT – better way to grow cells (outside the body) and use them as therapies

https://singularityhub.com/2019/07/30/scientists-just-released-a-new-playbook-for-engineering-longer-healthier-lives/

Playbook, described in Singularity Blog

Resveratrol

Promoted by David Sinclair, has financial stake, NAD boosters

” What is theoretically possible in the future remains unproven in humans and not ready for sale, experts say. “

Research by Sinclair and others helped spark interest in resveratrol, an ingredient in red wine, for its potential anti-aging properties. 

Sinclair co-founded a company, Sirtris, to test resveratrol’s potential benefits and declared in an interview with the journal Science it was “as close to a miraculous molecule as you can find.” GlaxoSmithKline bought the company in 2008 for $720 million. By the time Glaxo halted the research in 2010 because of underwhelming results with possible side effects, Sinclair had already received $8 million from the sale, according to Securities and Exchange Commission documents. He also had earned $297,000 a year in consulting fees from the company, according to The Wall Street Journal. (ok… XD)

“If you want to make money, hiring a sales rep to push something that hasn’t been tested is a really great strategy,” said Miller, who is testing substances on mice. “If instead you want to find drugs that work in people, you take a very different approach. It doesn’t involve sales pitches. It involves the long, laborious, slogging process of actually doing research.”

—

Top cited papers on google scholar:

Cancer chemopreventive activity of resveratrol, a natural product derived from grapes [1] 5,456 citations, Jang et al., 1997

mostly in mice / cultures

meta-study

most in mice, good effects

Resveratrol, a phytoalexin found in grapes and other food products, was purified and shown to have cancer chemopreventive activity in assays representing three major stages of carcinogenesis. Resveratrol was found to act as an antioxidant and antimutagen and to induce phase II drug-metabolizing enzymes (anti-initiation activity); it mediated anti-inflammatory effects and inhibited cyclooxygenase and hydroperoxidase functions (antipromotion activity); and it induced human promyelocytic leukemia cell differentiation (antiprogression activity). In addition, it inhibited the development of preneoplastic lesions in carcinogen-treated mouse mammary glands in culture and inhibited tumorigenesis in a mouse skin cancer model. These data suggest that resveratrol, a common constituent of the human diet, merits investigation as a potential cancer chemopreventive agent in humans.

—

Biological effects of resveratrol [2] 1741 citations

Full article not available, seems to be summary of research

” However, the bioavailability and metabolic pathways must be known before drawing any conclusions on the benefits of dietary resveratrol to health. “

—

Therapeutic potential of resveratrol: the in vivo evidence [3], 3315 citations, 2006

By Joseph A. Baur, and David A. Sinclair.

Resveratrol, a constituent of red wine, has long been suspected to have cardioprotective effects. Interest in this compound has been renewed in recent years, first from its identification as a chemopreventive agent for skin cancer, and subsequently from reports that it activates sirtuin deacetylases and extends the lifespans of lower organisms. Despite scepticism concerning its bioavailability, a growing body of in vivo evidence indicates that resveratrol has protective effects in rodent models of stress and disease. Here, we provide a comprehensive and critical review of the in vivo data on resveratrol, and consider its potential as a therapeutic for humans

Review of literature

Resveratrol has been considered to be a caloric restriction mimetic in lower organisms, primarily on the basis of its activation of sirtuin proteins and its capacity to extend lifespan9,14. In mammals, caloric restriction and resveratrol treatment afford protection against a similar spectrum of diseases (TABLE 1), justifying further investigation into the potential overlap in mechanism of action.

It is fair to say that the literature on resveratrol is, in many cases, contradictory and confusing. The wide range of concentrations and doses used to achieve the various effects reported for resveratrol (~32 nM–100 µM in vitro and ~100 ng–1,500 mg per kg (body weight) in animals) raises many questions about the concentrations that are achieved or achievable in vivo. Furthermore, resveratrol has a short initial half-life (~8–14 min for the primary molecule175,176) and is metabolized extensively in the body. As such, calculating the effective in vivo concentration of resveratrol or designing new studies based on the current literature can be daunting

In mammals, there is growing evidence that resveratrol can prevent or delay the onset of cancer, heart disease, ischaemic and chemically induced injuries, diabetes, pathological inflammation and viral infection. These effects are observed despite extremely low bioavailability and rapid clearance from the circulation. Administering higher doses to improve efficacy might not be possible as toxic effects have been observed at or above 1 g per kg (body weight)147. Moreover, administering a daily dose to a human weighing 75 kg with 100 mg per kg (body weight) of resveratrol would require 2.7 kg of resveratrol a year, at a current cost of about US$6,800. Therefore, blocking the metabolism of resveratrol, developing analogues with improved bioavailability, or finding new, more potent compounds that mimic its effects will become increasingly important.

However, activation of the mammalian Sir2 homologue SIRT1 by resveratrol has yet to be demonstrated in vivo, and our current lack of understanding of how caloric restriction brings about its effects precludes a more definitive mechanistic comparison

See references at the end for some good footnotes!

—

What about recent papers?

Mwah, nothing really good in humans…

https://khn.org/news/a-fountain-of-youth-pill-sure-if-youre-a-mouse/

Prof. dr. J.H.J. Jan Hoeijmakers

Jan Hendrik Jozef Hoeijmakers (Sevenum, 15 March 1951) is a Dutch molecular biologist, biochemist and molecular geneticist. He is known for his clarification of the DNA repair mechanisms and the effects of defects in the repair mechanism on genetic stability in old age, cancer and various hereditary disorders.

https://nl.wikipedia.org/wiki/Jan_Hoeijmakers

The team of Jan Hoeijmakers succeeded in cloning the first human DNA repair gene, Ercc1, followed by many more, discovered the very strong evolutionary conservation of DNA repair and an unexpected link with basal transcription.

His team identified which repair processes primarily protect from cancer and which from accelerated aging and succeeded in getting grip on the aging process in mice by modulating DNA repair and surprisingly by nutritional interventions. 

Rapid accumulation of unrepaired DNA damage in these mice may cause cancer or premature cell death and senescence, but triggers also an anti-aging, anti-cancer ‘survival response’ likely in an attempt to extend lifespan. 

In 2005 Hoeijmakers started a company called DNage and in 2012 he founded AgenD whose mission is to provide solutions for medical/health problems associated with aging. 

https://www.oncode.nl/research/groups/jan-hoeijmakers-group

Jan Hoeijmakers is Prof. Molecular Genetics at the Erasmus Medical Center in Rotterdam, the Netherlands. His research focuses on the mechanism and clinical impact of mammalian DNA repair. His team cloned half of the genes involved in nucleotide excision and transcription-coupled repair, enabling elucidation of the underlying molecular mechanisms, and generated the largest set of mouse repair mutants allowing insight into the etiology of human repair syndromes. He discovered that DNA damage and consequent transcription stress is a main cause of ageing and that dietary restriction dramatically delays accelerated aging in mouse repair mutants and corresponding human patients by reducing DNA damage. These findings have wide clinical implications for many aging-related diseases most strongly neurodegeneration, for reducing side effects of chemo- and radiotherapy, and ischemia reperfusion injury associated with surgery and organ transplantation. Jan Hoeijmakers heads research teams in the Erasmus Medical Center, the Princess Máxima Center for Pediatric Oncology in Utrecht and the CECAD in Cologne. For his scientific achievements Hoeijmakers has obtained many (inter)national awards and distinctions including the Spinoza award, Louis Jeantet Prize for Medicine in Europe, the Josephine Nefkens Prize for cancer research, 2 subsequent ERC advanced grants, the Koningin Wilhelmina Research Prize of the Dutch Cancer Society, recently the Thon Award of the Olav Thon Stiftelsen, etc.

https://ssiem2019.org/prof-dr-j-h-j-jan-hoeijmakers/

Articles

https://scholar.google.nl/scholar?hl=en&as_sdt=0%2C5&q=J.+H.+J.+Hoeijmakers&btnG=

Web archive, erasmus MC profile

https://web.archive.org/web/20170201220024/http://www.erasmusmc.nl/MScMM/faculty/CVs/hoeijmakers_cv?lang=en

Rapamycin

DEF

Article: Rapamycin directly activates lysosomal mucolipin TRP channels independent of mTOR

https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3000252

https://news.umich.edu/a-new-pathway-for-an-anti-aging-drug/

Rap and rapalogs promote autophagy via a TRPML1-dependent mechanism. Given the demonstrated roles of TRPML1 and TFEB in cellular clearance, we propose that lysosomal TRPML1 may contribute a significant portion to the in vivo neuroprotective and anti-aging effects of Rap via an augmentation of autophagy and lysosomal biogenesis.

• “If you look at the administration of rapamycin across about a billion years worth of evolutionary animal models, everything from yeast to worms, fruit flies to mammals (mice and dogs), this compound seems to universally increase life”
• Rapamycin binds to a complex, called mTOR (mechanistic target of rapamycin) in our cells and inhibits its function

• mTOR regulates autophagy
  • When mTOR activity is turned down (by taking rapamycin), the body is more likely to undergo autophagy
    • Autophagy is the process by which cells eat themselves – the dysfunctional cells (like cancer cells) tend to be “eaten” first
  • In a sense – the inhibition of mTOR mimics what happens to the body in a nutrient sparse environment
• Peter has been taking 5 mg of rapamycin for the last 3 months (he doesn’t specify how often, but it sounds like every 4-7 days)

• In the Mannick study, the negative side effects when taking 5 mg of rapamycin once per week, compared to taking 1 mg every day, didn’t seem to be that much worse
  • But taking 20 mg once per week vs. 5 mg once per week, showed no additional immune benefit (however there were more negative side effects)
• Matt Kaeberlein has done some studies on dogs, suggesting the optimal dosing in humans would be around 4-8 mg, in some sort of pulsatile/episodic fashion (every other day or every third day)
  • Why? – You don’t want to inhibit MTORC2 
    • If you dose with rapamycin every day, you don’t allow for TOR to be recirculated, and within a few days of consecutive dosing, you start to inhibit the creation of mTORC2
• So in short, there’s no side effects to taking too little (just a lack of benefit), but you want to be careful about taking too much
• If Peter were to guess the perfect dose: 4-6 mg every 4-7 days

• Rapamycin (a drug) acts on a protein called mTOR (it inhibits its function)
• Insulin, glucose, and amino acids activate mTOR
• mTOR is responsible for many things, but perhaps most important is its regulation of autophagy
• By suppressing mTOR through things like fasting, we increase autophagy
• Human data suggests that an intermittent dosing of rapamycin is most beneficial

It’s now known there are two mTOR complexes

• mTOR Complex 1 (mTORC1) centered around RPTOR
  • RPTOR = Regulatory Associated Protein of mTOR
  • By “centered around” – it just means “joined together with”
• mTOR Complex 2 (mTORC2) centered around RICTOR

A

https://podcastnotes.org/2018/08/14/mtor/

NMN

David takes 1 g of NMN and 0.5g of resveratrol every morning mixed in with some yogurt 

A new study published in Nature Metabolism finally reveals the answer to how NMN enters the cell in order to become NAD+ and that it does not need to convert into NR to do so.

Nicotinamide mononucleotide (NMN) is a biosynthetic precursor of nicotinamide adenine dinucleotide (NAD+) known to promote cellular NAD+ production and counteract age-associated pathologies associated with a decline in tissue NAD+ levels. How NMN is taken up into cells has not been entirely clear. Here we show that the Slc12a8 gene encodes a specific NMN transporter. We find that Slc12a8 is highly expressed and regulated by NAD+ in the mouse small intestine. Slc12a8 knockdown abrogates the uptake of NMN in vitro and in vivo. We further show that Slc12a8 specifically transports NMN, but not nicotinamide riboside, and that NMN transport depends on the presence of sodium ion. Slc12a8 deficiency significantly decreases NAD+ levels in the jejunum and ileum, which is associated with reduced NMN uptake as traced by doubly labelled isotopic NMN. Finally, we observe that Slc12a8 expression is upregulated in the aged mouse ileum, which contributes to the maintenance of ileal NAD+ levels. Our work identifies a specific NMN transporter and demonstrates that Slc12a8 has a critical role in regulating intestinal NAD+ metabolism.

https://www.leafscience.org/nmn-crosses-cell-membrane/

NMN and Resveratrol Explained

• Sirtuins are genes found to control aging in yeast cells
  • There are 7 of them in humans (5 in yeast)
  • They protect all organisms from deterioration and disease
  • Sirtuins essentially “sense when we’re hungry/exercising, and send out the troops to defend us”
  • When you put more sirtuins into a yeast cell or a mouse, it lives 5-20% longer
• NMN and Resveratrol are molecules which essentially mimic the effects of the sirtuin genes
  • “You can think of resveratrol as the accelerator pedal for the sirtuin genes, and NMN as the fuel”
    • “Resveratrol steps on the accelerator pedal of the sirtuin enzymes”
  • So you need the fuel (NMN) for resveratrol to work
• You can buy NMN on Amazon
  • It’s sort of related to NR (nicotinamide riboside) – this raises NAD levels
• Sirtuins need NAD to work
  • “In fact, if you didn’t have NAD in your body you’d be dead in about 30 seconds”
  • As we get older, our NAD levels drop  – by the time you’re 50, your NAD levels are about half what they were when you were 20
  • NMN also boosts NAD levels (like NR)
• Why not just take NAD?
  • It’s taken up really poorly into cells (it’s a large molecule) – Dr. Peter Attia talked about this in these Podcast Notes
  • NMN is much smaller, and thus gets into cells easier

https://www.leafscience.org/nad-transporter-identified/

https://www.leafscience.org/nmn-crosses-cell-membrane/

https://www.nature.com/articles/s42255-018-0009-4

David Sinclair, director of Harvard’s Center for the Biology of Aging

“[In my lab] we’ve been working on the molecule NAD. We published in Cell in March that by raising NAD levels we could rapidly reverse many aspects of aging in mice. [We gave] old mice the ability to run like young mice again and actually out-compete young mice. That was happening because there was improved blood flow throughout the animal. The molecule that we used is called NMN. We put that in the water supply, and after just a week we saw an increase in endurance. We’re excited about this breakthrough because it shows that we understand why we lose blood flow as we get older, and why we get tired and feel frail. But it also shows that we have a very quick way of reversing that. You could imagine people who are tired, wheelchair-bound, or even bedridden, having energy to get out and exercise again.”

In Vitro & In Vivo

Many scientific paper refer to the way they have studie something as ‘in vitro’ or ‘in vivo’. What do these terms mean? What are the differences (with regards to research)? And what is an example of their use?

In vitro

In vitro studies are usually done with just a few cells in a controlled environment like a test tube or laboratory dish. In vitro is Latin for ‘within the glass’. This way researchers can look very specifically at only one process (and get more detailed results). Because of the relatively low costs and complexity, you can do many different experiments at low cost.

A downside is that in vitro studies may forgo the necessary complexity and ‘normal’ conditions that arise within a living organism. This is also called the absence of biokinetics: (the study of) the growth changes and movements that developing organisms undergo.

Examples of studies are those in microorganisms, cells, or biological molecules (proteins, DNA, RNA). For instance, you could study how RNA molecules bind to specific ligands (ion or molecule).

To better extrapolate from in vitro to in vivo you can do apply multiple techniques. You could increase the complexity of the in vitro system. Or you can use mathematical modelling to simulate a more complex system.

In vivo

In vivo studies are done in living organism. In vivo is Latin for ‘within the living’. An in vivo study can be done in animals (including humans), and plants. This way researchers can see the real-life effects of drugs and interventions. This could show that the effect doesn’t take place, or that other (negative) side-effects happen. The costs are higher than for in vitro, but you get a much more realistic experiment.

An example of an in vivo study is to see if the body actually absorbs the molecule or treatment. If it passes through your body without getting picked up, then modifications should maybe be made.

In vivo experiments are done in many different species. Of them the mouse is one of the best known. The roundworm c. elegans is another much used test subject. Of course in vivo experiments are also done on humans. Because each animal is different (had different metabolic processes) it doesn’t mean that something that works in vivo on one, does also work in the other.

How do they translate?

Not all experiments that yield the desired result in vitro, translate to in vivo outcomes. One reason could be that the molecule or drug is not able to reach the destination you want it to work in, for instance, because it can’t breach the blood-brain barrier.

The same caveat also applies to the difference between different animals used in in vivo experiments.

Currently, I couldn’t find useful/any data on how many studies translate from in vivo -> in vitro (yeast) -> in vitro (mouse) -> in vitro (human) (of course extra steps can be added or removed). I hope to update this part soon.

In silico studies

These tests are performed on a computer (simulation). The Latin here is the same as the English: silicon (chips). Although quite new, in silico techniques could help to find out how drugs interact with the body and with pathogens. Three ways this technique could be applied are:

1. Bacterial sequencing techniques – sequencing bacterial DNA and RNA to identify bacteria
2. Molecular modelling – how drugs interact with the nuclear receptors of cells
3. Whole cell simulations – simulating how a (bacterial) cell behaves in an environment

Sources

https://mpkb.org/home/patients/assessing_literature/in_vitro_studies

https://en.wikipedia.org/wiki/In_vitro

https://www.verywellhealth.com/what-does-in-vivo-and-in-vitro-mean-2249118

https://en.wikipedia.org/wiki/In_vivo

Why I Started Long Life

I’m very curious to see if we can lead longer healthy lives. I believe that this is one of the most interesting fields out there and one where I might contribute to. Longevity research might have a disproportionately large impact on the world. This blog is my first investigation into this field. Below I spell out my reasons in more depth.

Real Solutions to a Hard Problem

As far back as our history goes, people have been searching for the Fountain of Youth. We don’t want to become old (but see the next part) and so we’ve been searching for tools to tackle diseases (symptoms) and the whole ageing process itself (causes). Now that we’ve started to understand a part of our metabolism a bit better, we might stand a chance to tackle this.

Research in the lab and in animals is promising. Some mouses live twice as long before, some genes are identified in the ageing process (by deactivating them), and some prominent scientists (notably Aubrey de Grey) predict that we have a good shot at finding robust solutions to the causes of ageing in 20 years.

I Want to Live Forever

I can’t imagine myself wanting to grow old. To have pain everywhere, to battle cancer, to be in the hospital more than outside of it. Growing old has been romanticised and many people believe that it’s even good to have an expiry date. That motivates you to live a full life, right?

Well, I think that the opposite also is true. If we were to live to 150, 600, or forever, wouldn’t we take more care of the planet? Make better life decisions? Save more for the future?

And imagine the wisdom that we might accumulate. Think of the professors that don’t need to retire, the scientists that can keep on theorising, the chess grandmasters that can keep on learning. Think of the full life you can live, the countries you can visit, the love you might experience.

One of the inspirations for this blog has been this article: The Fable of the Dragon-Tyrant by Nick Bostrom. It uses the analogy of a dragon (for death) and how the people living under the dragon are used to sacrificing their family and friends to it. But what if we were able to stop the sacrifice, to keep your loved ones alive. Also, see this video by CGP Grey that summarised the article:

Longevity is Multidisciplinary

Another reason for my interest in longevity is the reason that it brings together many different disciplines. And I think that interesting research happens at the intersection of multiple areas.

For me, it brings together artificial intelligence (e.g. DeepMind doing protein folding, learning algorithms helping with drug discovery), biology (e.g. CRISPR), entrepreneurship (the many companies that have sprung up, and a chance for me to have an impact in this field), and ethics (e.g. who will get to live forever, “The future is already here — it’s just not very evenly distributed” – William Gibson) . Of course, it brings together many other fields, people, and ideas.

Now is the Time for Me

At Queal (where I’m the co-founder and CEO), we’re at a very good point and I’ve freed up some time to think about other ideas (about a day or so as of writing this). I will use this time to start an inquiry into what we (collectively) know about ageing and what we can do. At the start, I will first try and deduce what different areas/subtopics (e.g. molecular damage, dietary influences) there are, and what the latest knowledge is there. I will also focus on finding the right sources (news/scientific) to keep up with the latest discoveries.

I hope I’ve been able to give a good overview of my reasons for starting this blog. With that being said, I will leave you with this final note:

This is Why We Die

Most of us die from ageing. For every person that dies in a car accident, 34 have died from cancer, cardiovascular disease, diabetes, and other age-related diseases. Compared to homicide (105 to 1) and conflict (357 to 1) it’s even more striking[1].

Yet we don’t focus most of our energy on preventing age-related diseases. And maybe with good reason, one day we will die (probably). But what if we could extend our healthy lifespan by 10, 20, 50 or even more years. I for one think that is a very exciting possibility.

Today is the right time to start thinking about this, or as the Chinese would say: “The best time to plant a tree was 20 years ago, the second best time is now.” To the best of my knowledge, we are now at the point where we start to understand some of the underlying processes that cause ageing.

The elixer of life is now growing on the tree of knowledge and this is my first step at learning more about this.

Why We Die

With all that being said, here are the 7 reasons/categories why we die. I’ve taken these from Aubrey de Grey (wiki), a brilliant gerontologist/connector/promoter of the fight against ageing. Here we go:

1. Mutations – in chromosomes
   • this causes cancer due to changes in the nuclear DNA, proteins that bind to this, or molecules that contain genetic information in the eukaryotes
2. Mutations – in mitochondria
   • this causes problems in the energy-producing parts of a cell (the mitochondria), again these are changes to the (local) DNA
3. Junk – inside of cells
   • when the junk inside the cell is not being cleaned/digested properly neurodegenerative diseases rear their heads
4. Junk – outside of cells
   • the same but this time outside/in-between cells, Alzheimer’s senile plaques are the most well-known example of this
5. Cells – too few
   • some cells don’t get replaced (or too slowly) and this makes us weaker with age (Parkinson’s disease, immune system)
6. Cells – too many
   • the dead cells that don’t divide but also are in the way (senescence), they can block space for living cells or even secrete proteins that do harm
7. Extracellular protein crosslinks
   • cells are held together by linking proteins and when too many connections form, they lose elasticity

Which Diseases are Responsible?

If we look at it from another angle, the diseases that kill us, what is it that actually takes us out? All of them have links to the 7 systems described above, yet all in different ways, which I hope to describe in future in-depth blogs.

1. Cardiovascular diseases (18 million, 32%)
   • A class of diseases that involve the heart or blood vessels
   • “The most important determinant of cardiovascular health is a person’s age.”[2]
   • Related terms: caloric restriction (CR), sirtuins, IGF-1, rapamycin (mTOR)
2. Cancers (9 million, 17%)
   • A disease caused by an uncontrolled division of abnormal cells in a part of the body
   • “Ageing is the inevitable time-dependent decline in physiological organ function and is a major risk factor for cancer development. “[3]
   • Related terms: genomic instability, telomere attrition, epigenetic changes, loss of proteostasis, decreased nutrient sensing and altered metabolism, cellular senescence and stem cell function
3. Respiratory disease (3.5 million, 7%)
   • A type of disease that affects the lungs and other parts of the respiratory system. Includes asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, pneumonia, and lung cancer [4]
   • “The respiratory system undergoes various anatomical, physiological and immunological changes with age. The structural changes include chest wall and thoracic spine deformities which impairs the total respiratory system compliance leading to increase work of breathing .”[5]
   • Related terms: Stiffening of the thoracic cage (7th underlying principle), lower respiratory muscle strength (especially in men),
4. Diabetes, blood and endocrine disease (3 million, 6%)
   • A disease in which the body’s ability to produce or respond to the hormone insulin is impaired, resulting in abnormal metabolism of carbohydrates and elevated levels of glucose in the blood
   • “Almost one-third of U.S. adults over the age of 65 years have diabetes. Approximately half of those are undiagnosed, and an additional one-third of older adults have prediabetes.”[6]
   • Related terms: impaired glucose intolerance, postprandial hyperglycemia, defects in β-cell function, metformin
5. Lower respiratory infections (2.5 million, 4,5%)
   • Lower respiratory tract infections are any infections in the lungs or below the voice box. These include pneumonia, bronchitis, and tuberculosis
   • Viruses, bacteria, fungal infections, and mycoplasma are the main causes.
   • I guess this one is a bit of an odd one out, it’s not so much related to ageing as to health (in how strong your body is to overcome this). Also, the main burden of it is felt in subsahara Africa. [7]
6. Dementia (2.5 million, 4,5%)
   • Dementia is a general term for a decline in mental ability severe enough to interfere with daily life. Memory loss is an example. Alzheimer’s is the most common type of dementia
   • “Epidemiological studies have shown that dementia could be avoided even at extreme old ages.” The incidence of dementia has also gone down in the last few decades. [8,9]
   • Related terms: Amyloid-beta, microglia (CD22), P. gingivalis
7. Neonatal deaths (1.7 million, 3%)
   • The first cause on the list that is not directly related to ageing
   • Neonatal deaths are all the children that die in the first month
   • This has fallen dramatically from 140/1000 (14%) to 5/1000 (0,5%) of births [10]
8. Diarrheal diseases (1.7 million, 3%)
   • The second cause on the list that is not directly related to ageing
   • Diarrheal diseases are a collection of diseases caused by multiple viral, bacterial, and parasitic organisms that share the common symptom of diarrhoea, defined as the passage of three or more loose or liquid stools per day
   • Especially kids and the elderly are the most at risk (thus in a way linking it to ageing, at least for the latter group)
9. Road incidents (1.3 million, 2%)
   • Not related to ageing, and unfortunately something that hasn’t gone down over the last 10 years
   • It has gone down in some countries (e.g. Germany) where safety measures prevent deaths
   • The most vulnerable group is in the 70+ bracket (35/100.000 people)
10. Liver disease (1.3 million, 2%)
    • Not strictly related to ageing, but damage over time may lead to liver cancer

Together this top 10 causes of death cover approximately 85% of deaths. If we remove all those not strictly related to ageing, we still have 73% of deaths that are related to ageing directly.

Other Causes?

I think this list doesn’t cover everything we think of when we image death. Two things are missing that many relate to deaths. The first is war/conflict/terrorism [11]. The second is our lifestyle.

War used to be a much more common cause of death. Until the 20th century, most countries were at war, not at peace. The peak in the last 100 years was the second world war, with 22 deaths per 100.000. Today it stands at just over 1 per 100.000.

Our lifestyle is not something to boast about. Obesity stands at 13% worldwide, and at 28% in North America and Europe [12]. And I think that this can be one of the causes/co-factors of many of the causes of death listed above. Together with air pollution, bad diets, no exercise and other lifestyle related choices, we should count ourselves lucky that we’re actually living this long.

In this post I’ve explored the causes of death and looked at the diseases that eventually tackle us. I’m optimistic that we will find solutions to most, if not all, of these in the coming decades. Our solutions should be combined with an approach in which we also make sure we do our best to keep our body healthy through diet and exercise.

To end a short analogy. Imagine yourself as a car. If you run it down, put in the wrong fuel, and eventually drive it total loss in a car accident, you would be a very irresponsible driver. If you take good care of your car, change the oil when needed, and sometimes push the peddle to the floor for just a sprint, then you might have a longer journey ahead. If then someone comes along and replaces a part of the car, or gives it a special fuel that restores the engine, you might be driving the car for a very long time to come.

Longevity Websites

In my first exploration of longevity, I’m looking at who is doing what already. Here is an (incomplete) list:

Websites/Community/Non-profit

https://www.sens.org/ – SENS Research Foundation, research, education, outreach

https://www.lifespan.io/ – Website for funding research projects, blogs, and a great Rejuvenation Roadmap

https://www.reddit.com/r/longevity/top/?t=week – Subreddit for longvity, good (read: critical) comments (sorted by new)

https://neo.life/ – Original reporting on ageing (and a bit wider), by Jane Metcalfe, found via this article on Longevity as the greatest investment

https://www.longevity.international/ – Online platform, under construction, backed by Longevity International Consortium, Biogerontology Research Foundation, Aging Analytics Agency and Deep Knowledge Life Sciences, good overviews (summary here)

Companies

http://www.gerostatealpha.com/ – Gerostate Alpha – 3 well-known researchers

https://www.calicolabs.com/ – Calico, backed by Alphabet, no products, some turnover, $1.5b research center

https://verily.com/ – Verily, backed by Alphabet, $1.8b funding, work on monitoring, interventions, precise medicine (not root causes?)

https://unitybiotechnology.com/ – Unity Biotech, developing medicines that potentially halt, slow or reverse age-associated diseases, while restoring human health. Senolytic medicines

https://www.springdisc.com/ – Spring Discovery, machine learning for ageing research, $18m+ funding

https://insilico.com/ – Insilico Medicine, artificial intelligence for drug discovery, biomarker development & ageing research

https://www.longevity.vc/ – Longevity Fund, venture capital investing in longevity research

https://www.juvenescence.ai/ – Juvenescence, drug development and artificial intelligence (AI) company focused on ageing and age-related diseases. (parent company)

Other

https://ourworldindata.org/ – Research and interactive data visualizations to understand the world’s largest problems

https://en.wikipedia.org/wiki/Outline_of_life_extension – Wikipedia overview, and here an index of related topics

https://www.ldeming.com/longevityfaq#explanation – Laura Demin (Longevity Fund) explanation of ageing research

https://www.bluezones.com/ – Based on the Blue Zones (where people live long), correlation?, and only small effect

Older / Less Active

http://aginginmotion.org/blog/ – Advancing research and treatment of sarcopenia and age-related functional decline

https://joshmitteldorf.scienceblog.com/index-to-this-blog/ – Blog by Josh Mitteldorf (started September 2012)

http://act-ad.org/ – Accelerate Cure / Treatments for Alzheimer’s Disease

https://agingportfolio.org/ – Knowledge bank on ageing research, from 2011 (not active?)

https://www.agingresearch.org/about-us/ – Aliance for aging research (founded in 1986), infographic

http://www.anti-agingfirewalls.com/ – A weblog on the sciences and practices of living healthily very long by Vince Giuliano

http://www.brainpreservation.org/ – Brain Preservation Foundation (BPF), whole brain preservation (price, mammal brain preserved)

https://www.crsociety.org/ – Caloric restriction, old forum (still active), with some good posts

http://ageing-research.blogspot.com/ – Cellular Senescence blog – last post start 2018

More Organisations

https://www.afar.org/ – American Federation for Aging Research (AFAR), business organisation (B2B)/promoter, metformin trail

https://www.asaging.org/ – American Society on Aging, business organisation (B2B), more focus on quality of life

https://www.americanagingassociation.org/ – American Aging Association, business organisation (B2B), dedicated to understanding the basic mechanisms of aging in order to enable humankind to preserve and restore functions typically lost to age-related degeneration, and to extend the healthy human lifespan, linked to AFAR

https://www.a4m.com/ – American Academy of Anti-Aging Medicine (A4M), also Metabolic Medical Institute (MMI)

https://alliancerm.org/ – Alliance for Regenerative Medicine (ARM), development of safe and effective regenerative medicines and advanced therapies worldwide

http://bsra.org.uk/ – British Society for Research on Ageing (BSRA), promotion an d funding for causes and effects of ageing

http://www.cellage.org/ – CellAge, destroy aged cells, didn’t get of the ground?

https://www.churchofperpetuallife.org/ – Church of Perpetual Life (faith in technology, interesting/old website)

http://www.rlecoalition.com/ – Coalition for Radical Life Extension, conferences on radical life extension

https://www.cohbar.com/ – CohBar is a clinical stage biotechnology company whose mission is to increase healthy lifespan by developing treatments for the underlying metabolic dysfunction driving the diseases of ageing

https://dogagingproject.org/ – Dog Aging Project, study of ageing in dogs with rapamycin as possible drug