My Philosophy

On this page, I want to define, as far as possible, my philosophy or view on life in some (core) concepts. This probably is incomplete and something that will change over time (see changelog below). Yet still, I think it’s good to get a better grip on these concepts to be better able to express why I’m thinking what (and taking actions based on this).

Lastly, I know that in most actions during our lives we don’t think this way. We don’t reason from first principles or weigh actions based on expected utility. We make decisions based on gut feelings, heuristics, experience.

Still, with time I think that we/I may be able to make more decisions based on these concepts. And many decisions are those that have an influence on a longer time horizon (e.g. not eating meat).

One final reason for making this page is the following from Karl Popper (video): “State your theses clearly so they can be refuted.” Said as a critique on philosophers that hide behind definitions, difficult language, and theory (not reality).

How to Think

Critical Rationalism

This is a theory on how knowledge grows. Knowledge is tentative solutions to problems (so no definitive ‘truth’). It grows through correcting errors.

This is contrasted with reasoning by induction (general principles from specific observations).

This is mostly based on ‘Conjectures and Refutations‘ by Karl Popper. He would call it fallibilism (we can’t know what is true, but our theories can get closer). And the books by David Deutsch and subsequent analysis by Brett Hall.

This means that knowledge grows by making conjectures (that we creatively make up) and then test them (refutations). The one with the least amount of holes is our current best understanding of the world (e.g. the theory of relativity).

Knowledge (thus) grows cumulatively. It builds on the earlier theories, and improves them. This is gradual (not revolutionary).

Also see this twitter thread explaining it (better).

Sceptic

Always test knowledge. Ask why. Dogma or arguments from authority don’t count.

And even be sceptical of your own experiences. Your memory is bad (link?) and our brains are made to recognise danger on the Savanna, not to be rational. I.e. if you see a ghost, it was there in your brain, but Casper was not floating there.

Bayesian

Update your beliefs based on conditional probability. This is especially useful (and counter intuitive) when thinking about test outcomes and (false) positives/negatives. (UPDATE THIS TO BE BETTER XD)

See this amazing intro sequence.

Our Maps are Only Approximations

  • universe is flat, maps have levels

Nothing Surprising Ever Happened

  • RAIZ

Free Will

Yes, I have the ability to do what I desire. But no, I don’t have the ability to choose what I desire.

This doesn’t take away my responsibility (at the human level).

TBD

Consciousness

TBD

The Status Quo is bad

How we’ve been doing things is probably not the optimal way. We should be more eager to change/update based on new information.

There is something to be said for conservatism (e.g. in complex systems), but more probably we should reason from first principles and do what comes out on top.

First Principles

  • tbd, Musk

How to Care

Effective Altruism

We should reduce suffering (negative utilitarianism). Which is much more urgent/easier/uncontroversial than maximising happiness.

This can be done on the cheap. Some interventions are much more effective than others. So give money to those interventions.

See my much longer page on Effective Altruism here.

Compassion > Empathy

We can put ourselves in the shoes of someone else (empathy). We care, and should care, about the people around us. But empathy is a spotlight.

We should care not based on geography, skin colour, or cuteness. We should care without these qualifiers, we should be compassionate (feel for others, not feel with others).

Note: See ‘Against Empathy‘ by Paul Bloom for more, and the Wikipedia definition of compassion (I think) is more in line with how I understand empathy (feeling with).

Life is Getting Better

  • Singer
  • Harari

We Shouldn’t Eat Animals

  • Part of EA maybe
  • Ethical (argument why sentient)
  • Link to longer post
  • We can’t do it right

How the Universe Works

Darwinian Evolution

  • Dawkins en Dennett

There is No Universal Time

  • local

We Live in an Always Splitting Multiverse

  • Deutsch
  • End of RAIZ

How the World Works

  • (multiple?)
  • We all don’t know what is going on
    • no conspiracy/cabal
    • not like evolution (we look forward) but close to it

The Near Future

  • Gene editing
  • Ageing done
  • AI (timelines), which may kill us all
  • Killing animals is bad
  • Mars and beyond (asteroid mining, Deutsch matter in space)
  • We Learn facts, not thinking (jobs will change (more)?)
  • Automation will take many jobs (uncertain how much will come back, and you need schooling for that)

How Humans Work

  • We do things because others do them (so be skeptical of that)

Change Log

This page was made in late August 2020 for the first time. I will update the change log when I significantly update a concept, or add a new concept.

Ginger Drink

To start the ginger drink (with a ginger bug), and to keep it alive, do this:

  1. Add a cup of water (230g) into a medium-sized jar (1,5x cup of water at least)
  2. Add 3 tsp grated (in food processor) ginger
  3. Add 2 tsp sugar
  4. Stir (multiple times per day)
  5. Repeat 2-4 daily, until it starts to fizz (close jar if needed)
    • Total ginger ~250g, total sugar ~150g

To make a ginger drink:

  1. Juice 30g ginger (or blend really-really well, can juice with garlic press too, but 30g is a lot) into a large jar (2 litres+)
  2. Add 1-2 juiced lemons
  3. Add 1.6 litres of water
  4. Add 150g sugar
  5. Add 15g of ginger bug (restock your ginger bug if needed)
  6. Taste-test!
  7. Let it ferment (1-7 days) until fizzy enough
    • Put it in the fridge when (almost) fizzy enough, so it ferments slower

Inspiration/tips:

Hummus

This is the basic recipe, see possible changes below:

  1. Soak 150g raw (dried) chickpeas for at least 8 hours (e.g. overnight)
  2. Cook for at least 30 minutes (replenish water if needed) (add baking soda TO TEST)
  3. When done, drain and run cold water over them
  4. Put them (XXX grams?) into a food processor, together with
  5. 5 tbsp tahini
  6. 2 tsp lemon juice
  7. 10g salt
  8. 1 tsp garlic
  9. 1 tsp chili flakes (Ottolenghi)
  10. Add cold! water to the same height as ingredients
  11. Blend for at least 10 minutes!

Orange version:

  1. Add rass el hanout (and/or kurkuma)

Fresher version:

  1. Bake garlic & paprika (bell peppers) in oven before, with royal amount of olive oil over them (don’t add garlic powder)

Bean alternatives:

  • Mix chick peas with lentils, black beans, white beans, etc
  • (haven’t tested if any of them taste better, but variation doesn’t hurt)

Recipes to try:

  • https://cookieandkate.com/best-hummus-recipe/
    • Hmm, add a little baking soda to water when cooking chickpeas (so they become softer)
    • Hmm, cold water
    • Possibly add a bit of olive oil (good tasting one?)
    • Ground cumin
    • Variation: fresh leafy herbs
    • Variation: kalamata olives
    • Variation: sun-dried tomatoes
    • Garnish: olive oil, sesame seeds, chopped fresh parsley

Whole Wheat Bread

1. Mix together in a bowl, make blob:

  • 300 grams – whole wheat oat flour (volkoren tarwemeel)
  • 100 grams – oat flakes (haver vlokken)
  • 40 grams – crushed flaxseeds (buy in bulk packaging)
  • 40 grams – seeds and/or nuts
  • 10 grams – yeast (also buy in bulk)
  • 10 grams – salt (with iodine, not sea salt)
  • 250 grams – lukewarm water
    • dough should be soft but not too sticky, add more whole wheat if needed

2. Let it stand for 20 minutes

3. Spread it out on baking tray (powdered with oat flour), fold two sides together (left-right), then roll from another side (top or bottom)

  • Make about 3 cuts on the top so it can rise without breaking
  • Cover with hand towel

4. Let it stand for 40 minutes

  • Start oven (220 degrees) at 30 minutes into waiting time

5. Put in oven for 30 minutes

  • Let it cool under a hand towel afterward

Variations/tips:

  • Make two blobs (so you can freeze one of them, about 30 min after the end)
  • Add some raisins to the mix (or other dried berries-type things)
  • Make with (partly) white flour for more fluffy (less fibre-rich) bread

Stretching Plan

This sub-page of Fitness, documents my plan for stretching.

Morning (before breakfast)

Warm-up, namely:

  • Joint rotations from fingers to toes (wiggle, wiggle)
  • 10 squats
  • 10 standing cross-body toe touch
  • 10 jumping jacks
  • 10 reverse-lunges

Dynamic stretches (decrease over time), namely:

  • Arm circles (4×10)
  • Arm swings front to back (4×10)
  • Leg swings, front (4×12 per side)
  • Leg swings, side (4×12 per side)
  • Leg swings, back (4×12 per side)
  • Standing bend to front / lean-back (15x)

Before sports

Warm-up (same as above)

Dynamic stretches (same as above)

Weightlifting specific stretches, namely:

  • Pass-through with pvc (10, lx5, rx5)
  • Cossack squat (10x l-to-r-to-l)
  • KB/barbell on knee stretch (2×10 per side)
  • Slow ATG squats + reach (10x, can hold onto rack)
  • Rotator cuffs (1.25kg)
  • Slow mountain climbers (10x per side)
  • Thoracic extension (1 min total)
  • Snatch progression (3x per position)

After sports (4x p/w, Mo/We/Fr/Su)

Isometric stretches (one per body part, choose from list):

How to: 5sec tension, 3sec rest, 5 reps, 30sec end, rest 1min, x3 sets

Start with shorter (end) time of tension, increase over time

  • Shoulders: lay face down, arms forward stretched, raise thumbs up OR
  • Shoulders: lay face down, arms 90 degrees, raise hands
  • Shoulders: stand, hold pvc pipe at shoulder width, move overhead
  • Shoulders: stand, hold pvc pipe behind back, hands up/down get closer
  • Trunk/Back: foam roll on back, PNF tension OR
  • Trunk: stand, move upper body sideways OR
  • Trunk: sit or sit on knee, twist sideways
  • Abdomen: lay on front, move upper body up OR
  • Abdomen: same, but grab feet too
  • Inner thigh: middle split PNF hold OR
  • Inner thigh: sumo squat OR
  • Inner thigh: sit on knee and hands, raise one leg sideways (pissing dog) OR
  • Outer thigh: lay on back, one leg across, with band OR
  • Outer thigh: sit one knee bend forward, other leg behind, bend over OR
  • Outer thigh/Hip: sit with legs in 90degrees, lift back foot
  • Front thigh/Hip: one knee forward, other leg back, stretch hip forward OR
  • Front thigh: stand, fold one leg backwards, pull back (upper body can go forward)
  • Front thigh: sit on knee and foot, move hips forward OR
  • Front thigh: stand, pull foot backward (lean forwards) OR
  • Front thigh: sit on knee and foot, pull foot backward
  • Front thigh/Hamstrings: middle split PNF
  • Hamstrings: stand or sit, grab foot, pull it towards you OR
  • Hamstring: lay on back, pull feet towards face OR
  • Hamstring: stand, foot on table, tilt upper body forwards / back leg backward OR
  • Hamstrings/Back: Sit and pull upper body forward (pancake)
  • Calf/Ankle: KB/barbell on knee stretch OR
  • Calf/Ankle: bend over, grab foot, pull it towards you OR
  • Calf/Ankle: stand on stairs, one foot, push heel down OR
  • Calf/Ankle: stand on stairs, one foot, push knee forward

Relaxed stretches (optional):

How to: 30 sec in deep position, can repeat after 60 sec rest (180 sec better?)

  • Shoulders: sit on hands and knees, hands forward, chest down
  • Calf/hamstring: sit, pull toes towards face
  • Inner thigh: lay in split position with support OR
  • Inner thigh: lotus position (not with hands)
  • Hamstrings: stand/bend/lay and pull foot towards face
  • Front thigh: stand and pull knee backwards OR
  • Front thigh: sit on knees, butt on foot, lean backward
  • Back: foam roll
  • Ankle/Hip: deep squat
  • Ankle/Hamstring: Cossack squat

Walk it off (5 minute walk)

Non-sport days (afternoon)

Dynamic stretches (same as above)

Relaxed stretches (same as above or follow-along)

Making Music

This is the essay for the third theme of my 2020 goals.

I’ve always appreciated good music and have a very diverse set of musical genres that I like to listen to. For some years I’ve played saxophone and someday (when not living in the city) I hope to resume doing that.

Next to playing the saxophone, I haven’t really made music myself. Because I enjoy electronic music (techno, house, etc), I plan on learning how to make some of that myself.

This reminds me of a time when I was about 14 years old. My brother and I got a dj-set on which you could mix music together. We used it for a while but sold it to a friend within a year or two. The friend eventually became quite a reasonable dj.

My two goals for this project are, 1) be able to create music myself, 2) by this process learn to enjoy/appreciate music even more (by knowing what goes on ‘behind the curtain’).

Plan of Attack

  1. Find a program to make it in (I now have FL Studio 20)
  2. Find tutorials on how to use the program
  3. Find samples/edit them and make my first song
  4. Make more songs with these ideas:
    1. Classical music and techno beats
    2. Melodic vocals and techno beats
    3. Movie/tv series quotes and techno beats
    4. A more funky ‘tropical house’ beat
    5. Synthesizer number
  5. Find a way to easily host them (e.g. on this site and/or soundcloud)
  6. Design a workflow/system that I can keep on making music after this initial project is done

What I’ve Learned

I’m subscribed to SkillShare (referral link) and there I’ve found over 10 courses for FL Studio 20. I’m going to start with ‘FL Studio 20 Beginners Course – Learn How to Make Beats in FL Studio’

First session: 1.5h

  • Select ASIO driver (f10, audio), you can change the version if one doesn’t work well
  • Increase buffer length (f10, then audio, buffer) if the pc can’t keep up. Smaller buffer length if pc can do it well
  • Resampling quality (can do lower quality whilst making it (f10, audio)), put at maximum when exporting song
  • Undo history at 100 (f10, general), knob tweaks also enabled (both were already at this setting)
  • Autosave frequently – because chance of crashing highest during playback (f10, file) and changed save folder to large drive (D)
  • Press f1 to go to help (webpage by FL Studio)
  • How does it work?
    • You create patterns, loops
    • You add these to the playlist, this creates the song
    • You choose when and where the patterns play (arrange them)
    • In the mixer you can adjust the loops (mastering, audio painting, transition, filters)
  • If you have your own sounds, you can drag them into the ‘browser’ (on the left), just drag the folder there
  • F2 – rename and colour a pattern (loop)
  • Ctrl + x (when selecting parts of your loop, you cut them)
  • F4 – new pattern
  • + / – go to next / previous pattern (1-9 ditto)
  • ! paste in snares etc (in your pattern – from other pattern)
  • play buttons – channel rack (is only pattern), playlist (is all)
  • ! Bar at top of pattern is (I think, looks different than tutorial) how much they ‘miss’ the perfect mark
  • Shift + ctrl + c = clone a pattern (or right click on the pattern name (in top bar)
  • If you have an instrument, right click on it to go to piano roll
  • Ctrl + click (slepen) is highlighting
  • Shift + click to duplicate that what you selected

Second session: 1h

  • Middle-mouse click on loop to rename (and colour – F2 when that is selected)
  • Knobs on left of loops are left-right (first knob), and volume (second knob)
    • Panning can also be done in in mixer
  • Highlight sounds (loops) by left/right-click, alt (arrow up/down), shift+click, clicking on them (so everything that makes sense)
    • If multiple selected, can do gradient
  • In the mixer (down), you can assign your sounds, shift+ctrl+l and start from your first/top sound (auto-fills the rest after that)
  • Alt+delete (is delete loop)
  • If you drop a sound, drop it at bottom or in between other sounds (otherwise it overwrites the other one)
  • In loop/channel-panel, the III (three bars) icon is where you can make the sounds/tunes more human (same as thing in piano roll (bottom)) – called the graph editor
  • In loop/channel-panel – you have a loop feature (somewhat confusing – looping stuff that isn’t as long as everything or something)
  • (that was step-sequencer, now playlist)
  • Ctrl+a, del = empty whole playlist
  • select patterns with number pad (1,2,3)
  • then plus (or minus) to go to next/previous pattern
  • hover over top bar (with numbers), ctrl+click-hold to select that part, ctrl+b to copy-past that part
  • magnet (also top bar), you can select beat/bar to change where the loops snap to (how fine-grained)
  • (working with audio clips), good, but for drums etc use fl studio things (not audio clips)
  • alt (and move a loop in playlist freely) instead of snapping to the ‘grids’
  • alt+shift (right side), you can cut a part (and then delete the part you don’t want with right mouse)
  • Shift+Q, quantise = snap to grid

Third session: 1.5h

(piano roll)

  • F7 to open, ENTER to make full screen
  • Quarter beat/half-step (in magnet) to show the right amount of zoom/snaps (shift to mini-adjust time, alt to mini-adjust volume)
  • Ctrl+q is making everything snap (quantize) to gridlines
  • (trying out some things in piano roll)
  • if ghost notes enabled, double-right-click on notes to go to the other (ghost) instrument
  • via edit, allow resizing from the left (seems reasonable)
  • control (bottom) can adjust volume and pan (alt and hover over note you want to edit)
  • Not too useful for piano/guitar, but can be cool for snare or other things you want to edit in volume/pitch

(how to use the mixer)

  • Route sound (loop) to mixer (d/q to play that sound and check if the volume etc is moving on the right mixer)
  • ctrl+shift = higlighting multiple mixers
  • dry signal, going to master directly, wet signal is one that is going via other mixer (e.g. the reverb)
  • “mixer takes beat (loops) to next level

Fourth session (75min):

(sounds)

  • Make folder where you save everything
  • Be organized
  • Buy/have some sounds, but don’t need too many
  • (downloaded and unzipped some drum kits)

Fifth session (45min):

(plugins, backups, snaps)

  • More technical discussion things

Good info for first song: https://www.youtube.com/watch?v=2AXzP3hs98g

Green Roof & Solar Panels

Why: Because our bedroom gets really hot in the summer. A green roof might help. Solar panels too, and of course will give us sustainable energy.

The questions I want answered:

How much does a green roof help with heat?

Not really clear from websites. But do all say that is has this effect and also keeps in the heat in the winter.

Best info here (Living Roofs). Heat under roof is not 32, but 17 C.

How much does a green roof costs? Could I get the neighbour(s) involved?

This website (GroenDak) looks best. Here is an instruction on how to put it on the roof yourself.

Costs are €41 per m2 (DIY)

Roof is m2 (or m2 if only our own part)

How much do solar panels cost? How does long does it to earn them back?

Based on zonnepanelen.net website calculator (which first gobbles up your email and then wants more).

3200 kWh per year energy based on 12 panels.

That is very good, our usage is 1700 kWh or lower.

Size of panel is 165- or 196x99cm (so about 2m2).

€60 euro per month savings/money earned (guesstimate).

Based on GroenDak website, costs are around €2500 for 8 panels.

Can I combine both?

Coolblue says no (for green roof and installing solar panels).

Is there a subsidie available?

This one for green roofs Rotterdam. (links to this page)

  • €15 per square meter
  • 8 weeks after improvement (or earlier)
  • minimal 20 m2 (roof is possibly a bit larger than that)

Dog Food

Max is currently eating Acana dog food. I wanted to know if it would be easier/cheaper to make it myself (and make it vegetarian). After researching that, I eventually found out that the best solution is to buy vegetarian dog food.

I first dismissed the latter because I thought that this would be much more expensive. Only at the end of my research, I found out that the vegetarian dog food was cheaper than the one I was buying until now.

Previously – Acana

80 euro per bag of 17kg

€4,71 per kg

€1,13 estimated costs per day

DIY

€2,10 estimated costs per day

Based on list of ingredients adapted from this blog.

The mix I made consisted of 23% protein.

The costs per 700kcal would be €1,82 (so per ‘normal’ meal, so not too expensive and quite healthy)

(for myself: file is saved under personal – archive)

New – V-Dog Flakes / Crunchy Nuggets

53,50 per bag of 15kg

€3,57 per kg

€0,86 estimated costs per day

note 1: calories per gram estimated to be the same

note 2: Flakes is cheaper, but is Crunchy Nuggets are ‘brokjes’ so the same as Max has now

When I run out of the current food, I will be switching Max over to this food.

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

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
  • 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