podcast notes – Page 8

Podcast notes – David Sinclair and Matthew La Plante on brain health and brain aging

Hosts: David Sinclair and Matthew LaPlante

6.2M Americans over 65 living with dementia
This number will continue to grow

If you reverse aging, Alzheimers and dementia can go away, you can recover memories

Epi-genome – computer that reads the genome (genetic) software
Ex differentiation – when a cell begins to malfunction, forgets its proper role

Horvath clock – your biological (aging) clock
Measures DNA methylation
Can measure this for a dollar
Measured 112 yo woman, and brain organs were much younger than all others

Brain ages slower than rest of body
Partially due to protective barrier (skulls)
Brain cellular turnover is low
Volume of brain after 40 reduces 5% per decade

For most of history, we only really needed brain until 40s / 50s – but now we live until 70s / 80s
Our fast changing world – need to constantly learn and adapt, need more brain plasticity

3 longevity pathways that respond to adversity
1. M-tor
2. AMPK – low glucose
3. Sirtuins
They all work together, protect body
Proper lifestyle changes generally benefit all three

M-tor role in autophagy – recycling and garbage collection

Sirtuins – 7 genes in body
Sirt1 (sp?) seems most important for brain aging
Need to up-regulate sirtuins, can do it with NAD boosters, resveratrol

Diet and exercise
Mediterranean diet – very clear benefits to brain aging, proven to reverse mild cognitive impairments, in fact its a spectrum the more Mediterranean your diet the better the outcomes
Olive oils (oleic acid, also in avocados), red wine (polyphenols, resveratrol), less red meat
Standard Western diet has much more fat and red meat

B-vitamins are important – especially vegetarians can be deficient
Aging is accelerated when lacking B-vitamins

Alcohol, smoking, also harmful – related to homo-cysteine

Doctors can see blood vessel lining in back of retina – if they see a lot of plaque, high chance of imminent heart attack / death

“Your eyes are your brain” – when you look at someone’s eyes, you’re looking at their brain

Fatty acids
Normal diets often lack omega3 fatty acids (like in fish) – help with wound healing, depression
Eat salmon, mackerel, sardines
If plant based, find ALA high foods – flax seeds, walnuts, linseed
Oleic acid in olive oil and avocados is important too
Seaweed

Why omega 3s?
Important fat compound in brain, insulating material for brain, protects against inflammation

Exercise
Even walking can > better memory and cognition
Activate sirtuins pathways
Relates to executive function
Study: 6 months of cardio exercise for 55+ showed dramatic improvement in aging indicators
Study: 10 weeks of strength exercise increased BDNF, marker of new nerve cells, brain re-growth
“Get moving before it’s too late”

Supplements
Metformin – AMPK activator (which also affects sirtuin pathway)
Fish study: metformin in their food > better performance on memory tests
Cells make more mitochondria, lower blood sugar in bloodstream
High blood sugar is bad for all tissues, especially cardiovascular system
2019 study: Metformin > 55% prevention in diabetes incidence
Metformin might directly impact NAD too
NAD levels go down over time, increasing degradation as we age
NAD boosters to help cognitive functioning, brain repair
2004 study: NAD-H treatment slowed Alzheimers

Sleep
Hypothalamus controls your daily rhythms
Sirt1 and NAD important role in your wake / sleep cycle
If you lose Sirt1 / NAD functioning, you won’t sleep well, age prematurely
As you get older, you lose ability to sleep
Intervene with diet, exercise, supplements
How to sleep well?
Supplements: MNN (sp?), magnesium, l-theanine
Get light right when you wake up
Can supplement with blue light machines
One night of sleep deprivation increases amyloid beta production by 5% (bad)
If you deprive rats of sleep, get diabetes in 2 weeks

Podcast notes – Neil Howe, author of The Fourth Turning – Blockworks

Host: Mike Ippolito
Guest: Neil Howe, author of The Fourth Turning, works at Hedgeye

Generational theory wasn’t popular after WW2
Rebounded in 1960s-70s – generational gap caused by Baby Boomers, who had very different values from the war generation
Boomers wanted to take over and challenge their parents
Boomers aren’t builders, but they’re very expressive

Co-wrote Fourth Turning w/ Bill Strauss
Both authors had written already about generational issues
Fourth Turning wanted to look at series of generational changes in American history
Didn’t expect cycles – it was an epiphany as they researched
Certain kinds of generations always follow others
Interdisciplinary approach, sociocultural cycles

“Gen X” wasn’t coined until 1992 – Material Girl, hip hop culture, didn’t like Boomers’ hypocrisy, jaundiced and cynical views

Major civic revolutions / upheavals once every ~80 years (average lifespan, called a “saeculum”)
Each generation is ~22 years, 4 of them = ~80-90 years
Every turning tends to end in a crisis
1770s American Revolution > 1860s Civil War > 1940s WW2 > 2020s

Mike:
“Want to rebel against our parents”
Ray Dalio’s long-term debt cycle (every 80 years, great deleveraging in financial markets)

Fourth Turning has lots of linkages with cycles in other fields – economics, culture
Re-aligning political elections occur in sync with these cycles

“It doesn’t look good at the moment”

Every time you have a crisis, every one who had a living memory of the last crisis is already gone – eg, WW2 forgot Civil War, today we forget WW2 and Great Depression

Every turning is a generation – ~20 years
Each turning is when you’re moving from childhood > young adulthood > mid life > elder
The whole social mood changes as each generation shifts

Fourth Turning is final phase, the “crisis phase”
A civic / reconstruction phase
Associated with scarcity, the Depression, the great wars, the revolutions
Periods of great disorder
Institutions have become sclerotic / dysfunctional
Need rejuvenation / forest fires to clear out the brush
Allow new resources and new institutions to flourish
Periods of tremendous social growth

“We always make our biggest changes during times of crisis” – after WW2 we established Social Security, Bretton Woods + IMF + World Bank
Same after Civil War – national currency system, transcontinental railroad, etc

Lots of tribalization today – red vs blue zones, extreme political opinions
More people think a civil war is likely
Fascism vs socialism
Participation in politics has skyrocketed – voter turnout, “Trump solved that problem”
Rapid deterioration of growth prospects for young Americans
Book “Big Sort” shows how Americans are geographically dividing by culture and politics

Now likelihood of a great power confrontation caused by Russia invasion of Ukraine

Our current Fourth Turning started in 2008 with Great Financial Crisis
This phase will extend to 2030
Very low GDP growth, inflated markets with QE and low rates, driven by Central Bank policies and MMT
Long-term inflation expectations are exploding
Powell wants to be Volcker now, must fight inflation

America has enormous deficits today – no more stimmy, higher interest rates, Ukraine conflict, China struggling – bleak picture
Fed can’t really intervene now to protect markets
After mid-term, likely both Houses will be Republican
Both parties don’t really have consensus leadership

Mike: “something eventually has to give” – but then there will be genuine improvement
Realized other great powers aren’t democracies – China, Russia

On youth:
They invented the word “millennial” – high school class of 2000 was initial cohort
Did book “Millennial Rising” – they’re special, risk averse, attached to parents, less crime, collective teamwork / organizing

Greatest distrust with democracy is among younger people – believe it empowers older / richer people – thus the move to collectivism

Podcast notes – The Economist overview of longevity and anti-aging research (Babbage)

Podcast: The Economist (Babbage)

Rich world life expectancy is 70+, increasing by average of 5 hours per day

Victorian times – terrible doctors, but great engineers – clean water, better nutrition – lifespan really improved

20th c – defeated many infectious diseases, antibiotics after WW2, another step change

Countries with highest lifespan – Southern Italy, Japan
“can get to 85 just by living like the Japanese”

Why do we age?
Genetic material gets damaged
Machinery of gene expression
Major cellular molecules – protein synthesis, mitochondria go wrong, proliferation of senescent cells

Aging is root cause of many diseases – cancer, cardiovascular, neuro degenerative
If we can combat these fundamental aging pathways, we can fight a lot of these diseases

Most promising is altering blood plasma
Parabiosis – mice blood systems being shared, old mice improves from sharing with young mice
(Gavin Belson from the show Silicon Valley)

Cellular rejuvenation – transcription factors (Yamanaka factors)
If you apply them to body cells, they will “take them back to factory settings”
Yamanaka – Japanese biologist, won Nobel Prize – creating pluripotent stem cells
Can create cells identical to your body’s cells for experimentation and treatment
Risk of uncontrolled proliferation (cancerous cells) if mis-used

New research shows you can reverse (some) epigenetic marks of aging
Treatment on old mice becoming metabolically younger, can repair skin wounds better, seem to be healthier, expect to live longer
Proof of concept stage

Silicon Valley
Altos Labs – $3B in funding, “world’s best financed startup company” – led by prominent researchers
Focus on Yamanaka factors and “integrated stress response”, cells that have gone AWOL – metabolic problems, diabetes, Parkinson’s
Trying to develop novel approach to diseases caused by cellular malfunction – indirectly improving aging
“Natural selection cares less and less about multi cellular organisms as they get older”

Heart attack – lost tissue isn’t replaced, a scar forms, causing loss of function, so the heart remodels, get larger, walls get thinner, can lead to heart failure
Today transplantation is only cure, life expectancy afterwards is only 10 years
Identify cell types in heart that can be stimulated to create more healthy tissue
Trying to restore embryonic cell development in adult hearts (eg, like epicardial cells)
“regrowing parts of the heart”
Identify high risk patients, give them pre-treatment (like a pill), to prime cells to heal / repair when heart attacks happen
Organoids – small organs in dish – multiple cell types – eventually “derive heart in a dish”

Unity Biotechnology
Senescent cells – “cells in your body that have turned against you”
Senescent cells cause damage to neighboring cells
It’s a slow insidious assault inside your body
Vision is take a pill, get rid of your body’s senescent cells
In mice, experiments to tag these cells and remove them – cognition better, improve health
Now research focus is on the eye – to improve vision, suffering macular degeneration / color loss

Much of this research may not extend lifespan but can extend healthspan – number of healthy quality years
Lot of these treatments work for everything except for your brain – more complex and unpredictable
“What do you do about the brain?”

Podcast notes – Hugh Jackman on Tim Ferriss show

Guest Hugh Jackman (Wolverine)
Host Tim Ferriss

Reads a book every morning with his wife Deb
books by Esther Perel, Seth Godin, David Brooks (Second Mountain)
makes a cup of coffee, takes cold shower, then reads and meditates together
read out loud to each other

Gifts these two books often:
EB White’s Here is New York
David Foster Wallace’s This Is Water
prefers gifting short books

Learned meditation at drama school
Does transcendental meditation – has a mantra to occupy the monkey mind
Like cloudy water that settles and then see crystal clear
Started at 23, did it very regularly twice a day

Natural energy that comes from being on stage
Tells his kids to find that joy in their lives
On Broadway, he has almost religious routines and rules – no alcohol, doesn’t go out after shows, can sleep 45 minutes after getting off stage
Says a small mantra, moment of silence, before he goes on stage

Has listened to Tim’s podcast for years, also Sam Harris
Got nervous before being a guest

Tim: Hugh is polite to everyone he meets

Mom left when he was 8, primarily raised by his dad
Dad said “your religion should be in your actions”
also “You cannot over invest in education”
always keep your word, very big on ethics
rarely gave Hugh advice, encourage him to make his own decisions

His wife acts purely from instinct / heart

Originally studied to be a journalist / communications
Was on debate team in school
Brother is successful barrister
Lots of debates at home – brother was Rhodes Scholar

Did a play in his last semester – got lead role
Spent 90% of his time doing it, and loved it
Surrounded by theater people, realized that was where he was meant to be
Went to study acting after that

Watched all of Ken Burns stuff during quarantine

If you start a business, you have to give it 7 days a week for 5 years
Being a professional actor is the same way
“Never wait for the phone to ring”
“get your brand out there and get going”
Started a theater company
Be wary of the word “career” – don’t take things for granted

Did Beauty & The Beast
Got weekly singing lessons
Was labelled as a singer, not an actor
Kept getting musicals offers – wasn’t getting film auditions
But kept working, learning, listen to his gut

Some calling beyond conscious brain, something elemental and instinctual, something you can find and hone
Working with life coach for 4 years – what are you here for? what do you really want to do?
Especially when you’re married / have kids – first priority is what’s best for your family

Universe gives you signs – accepted into acting school, cost $3.5K, didn’t have the money and didn’t want to ask dad, and then his grandmother passed and he got an inheritance of $3.5K

Tim: the most important personal examples of listening to intuition were when they didn’t make sense

Wife is into manifestation, he’s new to it
Greatest Showman – on fence about project; life coach told him he needed to commit one way or another; did visualization of how it could turn out, and went all-in – became a huge success
“Don’t insure yourself against failure”

Exercise
His most efficient / best exercise is the rowing machine
If you wanna get lean, row
Add in chest / pushups
That’s all you need to stay healthy and strong
Fighting is dance, not body building – there’s more relaxation than strength
if you told athletes to run at 85% max, they’ll often run faster than 100% – because they’re more relaxed

Before he does an activity, he imagines the feeling / outcome when it’s done – helps prepare him because he often suffers from insecurity / lack of confidence

Carl Lewis – at 50 meter mark, his form was exactly the same – whereas the other sprinters started to tighten, exert and push more

Loves puzzles and games
Wentworth 1000 piece puzzle is a good starter
Another form of meditation
Can stay up late into night doing them

Podcast notes – Maxine Clark (Build A Bear founder) on EconTalk with Russ Roberts

Maxine Clark – founded Build A Bear workshops – 25 year anniversary, started in 1997
Have other animals too – dogs, cats, fish, etc

Was in retail for 20+ years before BAB (former President of PayLess)
Started BAB in St Louis

Wanted to do something for children, engage their imaginations, but no one was doing it
Even in a zoo – trainers can touch animals but you’re not supposed to

Studying Beanie Babies – her friend Katie declared it was easy enough to make on their own
Maxine had lightbulb moment – why not let kids build their own? – started looking to buy a pet toy factory
Thought about naming the animals, but Katie suggested not naming them because each owner would want their own name

Customer experience
Disney-like experience, more like theme park than a typical retail store
Hardest choice is picking animal you wanna make
You can add sounds and scents (one of most popular scents is birthday cake)
Stuff bear, fluff it up, then it’s machine stitched for you (originally they were all hand stitched)
Then you name it, prints out a certificate of ownership
It’s a family experience
Popular birthday gift

Why are bears cuddly? Not true in real life
Teddy bear comes from 1902, president Teddy Roosevelt – hunting trip, saw 2 bears, would not shoot them, brought out kindness & empathy
A toy company proposed the idea of a toy “teddy bear” and the president endorsed it
In Germany at same time, similar concept was popularized

Bought patent for their unique fast sewing system

Have sold 200M+ bears

Birthday parties in-store were very popular

Lots of partnerships eg Girl Scout bears, Hello Kitty, etc

400 worldwide stores
Regular store is ~2500sf

Bears are neutral – no race, no political opinion
Everywhere in world, try to localize costumes and accessories

Hired a lot of teachers who worked part-time – great source of ideas and culture

Profitable in first few months of operation

One customer wanted to stuff their dog’s ashes into the bear
Another customer wanted to incorporate their child’s pacifier as a keepsake
Always try to accommodate special requests
“Yes” is our philosophy
Hire “huggable” people – employees who love children
Group interviews – watch them make bears, watch their enthusiasm and facial expressions

Store primary color is yellow – it’s the international color of the happy face

McDonalds – focus on process that ensures reliable quality no matter the employee, instead of on outstanding individual employees

stopped listening at 2/3 of episode