
Beginner's guide to longevity research - sajid
https://www.ldeming.com/longevityfaq
======
semi-extrinsic
I'll offer a contrarian view: longevity research, as in the current scope, is
about as accurate and useful as Ray Kurzweil's predictions from the 90s.

Let's take caloric restriction, for instance, which is all the rage. Trouble
is, all of the evidence we have is in mice or lesser animals, _and the
comparison is animals on caloric restriction against animals being force fed
to the point of obesity_. Let me repeat that: in research that shows caloric
restriction increasing lifespan in animal models, they are not comparing to
animals on a normal diet. So it's entirely plausible all this caloric
restriction research findings is just confirmation of the fact that obesity
shortens lifespans.

This isn't even touching on the point that correspondence between animal
models and humans is abysmally bad. It's the best we have, but there's a very
good reason drugs need to go through three stages of human testing after it's
been proven successful in animals. With caloric restriction, we don't even
have consistent positive results in monkeys, only in rodents.

Has any of this longevity stuff ever been tested in humans? Obviously not,
since it would take many decades.

Some pointers for further reading:

[https://www.sciencedirect.com/science/article/pii/S089158491...](https://www.sciencedirect.com/science/article/pii/S0891584914002317)

[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3765579/](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3765579/)

~~~
alexlikeits1999
While I agree with the general sentiment that CR is probably not very useful
for humans, I think you are either misinformed or exaggerating for the sake of
generating a response.

Ad-libitum feeding is not force feeding. Noone goes and shoves the food into
mice. The food is just available.

Also, CR has extended lives in many species, including dogs (see
[https://avmajournals.avma.org/doi/abs/10.2460/javma.2002.220...](https://avmajournals.avma.org/doi/abs/10.2460/javma.2002.220.1315)),
not just mice.

~~~
ianai
Eh I’ve seen how dogs eat. They will eat until they puke. Mice may be doing
the same.

~~~
kmonsen
Not sure why you are downvoted, most dogs are always really hungry and
different even from an obese human.

Also while comparison to animals can be useful as a starting point it is no
proof that it works anything like that in humans.

------
Jemmeh
This is a pretty fantastic writeup, short and simple on each topic with loads
of sources.

For those looking for something actionable, you may want to head to the reddit
board for intermittent fasting. It's a good way to lower your caloric intake
and increase autophagy. People doing intermittent fasting often also eat a
keto diet that is mentioned in the writing as well.

[https://www.reddit.com/r/intermittentfasting/](https://www.reddit.com/r/intermittentfasting/)
[https://www.reddit.com/r/keto/](https://www.reddit.com/r/keto/)

~~~
jbob2000
I have made many attempts at fasting. I'm skinny as a rake and get very weak
without some kind of constant caloric intake. I also get "hangry" and make bad
decisions on an empty stomach.

Is this just me? Or is this a thing that everyone has and just works through?

~~~
Jemmeh
1.) Start slow, you can start with something as short as 12hrs fasting
(sleeping time counts) and just add an hour to that every week or two.
Personally I added an hour as I get used to it. 14 hour fast and still not
hungry yet? I'll add an hour to it this week. Now I generally just eat one
meal per day unless I'm very active. 16hours fasting, 8 hours feeding window
is the most common spot for people to stop.

2.) This is exactly why people who do intermittent fasting are often eating
keto, which is a low carb, moderate protein, high fat diet. Carbs spike your
blood sugar. Then it comes crashing down and puts you in a relative "low", so
your body craves more of that quick energy and boom you are hungry/want carbs
again.

Fats and proteins on the other hand give you a more stable energy level by not
spiking your blood sugar as much. You stay full. The reason for only moderate
protein is because excess protein is also turned into glucose through
gluconeogenesis.

For the record my boyfriend is a black hole when it comes to food. He's fairly
muscular and active so he gets hungry pretty quickly. But if he eats keto
macros he can handle 1 meal a day too. He actually gets a bit sick eating carb
heavy meals now.

I've seen people do it without doing keto and still get weight loss success,
but a LCHF diet of some sort is the most common diet I see. Also the article
mentions specifically keto diet linked to longevity.

Read through the sidebar info on the keto reddit if you want an idea of where
to start.

~~~
jbob2000
Thanks for the encouraging response, I will definitely checkout the keto
subreddit.

~~~
Tenhundfeld
Yeah, came here to echo the idea that fasting is MUCH easier on a low carb
diet. If you start reading about keto, you'll probably see the classic macro
ratio of 75% fat, 20% protein, 5% carbohydrate – sometimes even higher
percentage from fat.

My advice is that starting out, I wouldn't get too hung up on the ratio. It's
actually pretty hard to get 75% of calories from fat. IMO, the important part
is to limit the carbs. If you're hitting something like 60% fat, 30% protein,
10% good carbs (mostly green veggies, maybe some berries), you'll still see
most of the keto benefits in terms of fewer mood swings and cravings, ability
to fast more easily, etc.

Healthy eating is one of those areas where a lot of people (myself included)
let perfect become the enemy of good. Even moderate low-carb, just eating
cutting out sweets and starches, can be enough for a lot of people to see
waistline and mood stability improvements.

------
reasonattlm
The author of this overview, Laura Deming, runs the Longevity Fund, and has a
research background in the study of aging. She merits congratulations for
being, I think, the first by a few years to put together a longevity-focused
fund, now joined by e.g. Jim Mellon's Juvenescence venture, Methuselah Fund,
Apollo Ventures, etc.

Rejuvenation research after the SENS Research Foundation model of repairing
the known root causes of aging is a massive arbitrage opportunity. It remains
the case that most people just don't get it, and are thus enormously
undervaluing research and companies in this space. That is changing in
senescent cell clearance, but six or seven other nascent areas of research and
development are in exactly the same position senescent cell clearance was in
back in 2010 - no attention, little funding, low valuation, huge potential for
breakout gains in said valuation on producing a technology demonstration for
rejuvenation in animal models.

It seems likely that the Longevity Fund will do well on the basis of having
invested in Unity Biotechnology alone, even putting aside any other successes.
The article linked here is a useful overview, with copious references, of the
type of work presently taking place in the aging research community. It well
illustrates that, aside from senescent cell clearance, nearly everything that
counts as a major interest by funding and number of scientists involved is a
form of tinkering with stress response biochemistry to modestly slow aging -
not addressing root cause molecular damage by repairing it, but rather messing
with metabolism to slow damage accumulation. Nowhere near as helpful.

Given what we know, where the data exists to compare outcomes between short-
lived and long-lived species, the approach of altering metabolic processes to
enhance beneficial stress response mechanisms is not going to move the needle
all that far in humans. The results should be exercise-like and calorie-
restriction-like in that they have worthwhile effects on long-term health,
assuming that the cost of development and treatment is low, but they won't add
much more to life expectancy than those two items are capable of achieving -
which means perhaps the low end of five to ten years at best in our species,
assuming life-long commitment to the intervention. Given that senescent cell
clearance is a going concern, and other damage repair approaches such as
cross-link breaking should follow in the years ahead, we can hope that the
focus of the research community will shift as other approaches prove
themselves much more cost-effective and successful.

------
Asdfbla
Very interesting research, but trying to derive actionable recommendations for
humans seems a bit laughable at this point. Still seems tough to become
immortal these days. Harvesting young blood, a rigid diet, castration and
starving yourself occasionally - lots of effort your self-absorbed wealthy
investor with a desire to live forever has to go through.

But then again, Sam Altman recently praised China for having fewer ethical
concerns in that regard, so maybe they will get some longitudinal human
studies going. The population scale full-genome analyses that are currently
underway might also be helpful.

~~~
reasonattlm
Actionable things for humans at the moment appear to look like trying
senolytic drug candidates in rational self-experimentation, with before/after
tests of metrics linked to tissue stiffness, inflammation, kidney and heart
function.

Clearing senescent cells very clearly produces a degree of rejuvenation in
mice, and can turn back progression of aging and specific age-related diseases
via a sizable number of metrics.

Of those senolytic drug candidates, dasatinib plus quercetin if you're fine
with short burst of chemotherapeutics, or FOXO4-DRI if you are fine with using
peptides lacking human data. Both of which should be filed under the "risk
that needs to be well understood" category. Or you could wait a few years for
the first human trials to run through and more data and better drug candidates
to arrive.

But these things are on the menu of possibilities, and are not expensive at
all to carry out as exploratory tests.

~~~
danieltillett
The problem with all potential senolytic drugs is cancer. Looking at all the
animal models (and spontaneous human mutations) where senescence is reduced
there is a corresponding increase in cancer. We really can't do much about
ageing until we can cure or prevent cancer.

~~~
reasonattlm
That would only be the case in the models where senescence is blocked
completely.

If instead for a short time killing some fraction of all currently existing
senescent cells, the effect on cancer risk should be a reduction, due to
decreased inflammatory signaling from those cells. The senescent cells that
are hanging around at any given moment in time aren't helping you in any way;
they're not reducing the risk of cancer. If there are enough of them, they are
in fact increasing the risk of cancer due to messing with the surrounding
environment. If those senescent cells ever actually helped, then that help was
applied at the time the cell became senescent - and shortly thereafter it
became a liability that should be destroyed.

There are emerging exceptions to that view, such as adaptive senescence in the
immune system and possibly in support cells in the brain, but fortunately both
of those should be largely moot points for the early senolytic therapies, and
don't seem to be obstacles in old mice.

------
the_economist
This is an awesome write-up.

Regarding the experiment on monkeys that showed calorie restriction led to a
longer life, there is one key point that I think damages the conclussion. Both
groups of monkeys were fed an extremely unhealthy diet that was very high in
sugar. So the conclusion would be that eating fewer unhealthy calories leads
to a longer life, not that calorie restriction in itself does.

------
agumonkey
"long" interview with aubrey de grey from last december:

[https://medium.com/@arielf/wake-up-people-its-time-to-aim-
hi...](https://medium.com/@arielf/wake-up-people-its-time-to-aim-
high-b0c2bcac53f1)

------
joekrill
Very interesting and informative! As someone who knows nothing about this
field, this was a really great summary! (I can only assume it's accurate
unless someone chimes in to claim otherwise).

------
jcmoscon
You guys should look at the "steak and eggs" diet. This is the best diet I
did. You loose a lot of weight, feel amazing, no brain fog, you do not get
crazy hungry. It's amazing!

~~~
raarts
That's because of the ketogenic aspect of it. Though I would get bored if I
only ate Steak & eggs.

~~~
jcmoscon
It's so easy you don't need to check how many carbs your food has because you
only eat steaks and eggs. You can change how you cook your eggs or get
different cuts of meat. And you can eat anything in the sixth day. It's the
easiest and most efficient diet I tried so far.

------
MMTP
Yes this is a great introduction into the topic. I would also recommend
checking out www.leafscience.org home of the LEAF foundation. They are the
guys who did that great video with Kurzgesagt last year and their website is
packed with great info about aging and research.

[https://www.youtube.com/watch?v=MjdpR-
TY6QU](https://www.youtube.com/watch?v=MjdpR-TY6QU)

------
cies
Really well written article! And a lot of things I've never heard of.

While keto is mentioned, I do think that another diet deserves a mention here:
WFPB (whole food plant based).

In the book, How Not To Die, Dr Greger bring together the science that
underpins this diet. Some one switching to this from a standard american diet
can expect to add some healthy years to their lives, based on sci evidence.

~~~
pdfernhout
Good point. See for example: The Whole Foods Diet: The Lifesaving Plan for
Health and Longevity" by John Mackey, Alona Pulde, Matthew Lederman"
[https://www.goodreads.com/book/show/34837239-the-whole-
foods...](https://www.goodreads.com/book/show/34837239-the-whole-foods-diet)

Based on research studies cited there, the typical US American stitching from
a SAD diet to a whole foods plant-based diet would live about ten years
longer, and additionally have a much healthier and happier twenty years or so
at the end with much lower likelihood of chronic illness or dementia.

See also: [https://bluezones.com/live-longer-
better/](https://bluezones.com/live-longer-better/)

For example: [https://bluezones.com/exploration/loma-linda-
california/](https://bluezones.com/exploration/loma-linda-california/) "Today,
a community of about 9,000 Adventists in the Loma Linda area are the core of
America’s Blue Zone region. They live as much as a decade longer than the rest
of us, and much of their longevity can be attributed to vegetarianism and
regular exercise. ... Adventists tend to spend time with lots of other
Adventists. They find well-being by sharing each other’s values and supporting
each other’s habits."

But even as good diet is essential, it is aspects of community and
infrastructure that help people keep eating healthy together. Likewise,
community and infrastructure can help promote daily exercise. So, ultimately,
for most people, longevity is not an individual thing. It is a community
thing.

That point on community is also made in the sequel to "Fat, Sick and Nearly
Dead":
[https://en.wikipedia.org/wiki/Fat,_Sick_and_Nearly_Dead](https://en.wikipedia.org/wiki/Fat,_Sick_and_Nearly_Dead)
and is even made by Dean Ornish in the trailer:
[http://www.fatsickandnearlydead2.com/](http://www.fatsickandnearlydead2.com/)

------
onuralp
I recommend Peter Attia's highly engaging and informative talk [0] on the same
topic, which I think does a better job at articulating the motivation behind
possible approaches to attacking the issue of health- and life-span.

[0]
[https://www.youtube.com/watch?v=vDFxdkck354](https://www.youtube.com/watch?v=vDFxdkck354)

~~~
roystonvassey
I second this. I think Attia is one of the clearest thinkers on health,
longevity and nutrition currently. Moreover, he is a trained doctor AND an ex-
McKinsey consultant, a combination that marries a strongly analytical and
numerical lens to a field (medicine) that notoriously isn't.

------
ldeming
Thanks everyone for reading! I'll be around if you have any questions.

~~~
beefman
I have 3 questions:

1\. Did you see the Park et al report on DNA-PK inhibition from earlier this
year?
[https://news.ycombinator.com/item?id=14301878](https://news.ycombinator.com/item?id=14301878)

2\. Is anyone working on sleep?
[https://twitter.com/clumma/status/764842049199898624](https://twitter.com/clumma/status/764842049199898624)

3\. Have you considered funding low-dose ionizing radiation research?
[https://www.facebook.com/clumma/activity/10151804061151737](https://www.facebook.com/clumma/activity/10151804061151737)

------
robbomacrae
It would be interesting to see a lab focussed on reproducing these findings
and then running all the various combinations to see how those incremental
improvements stack. Seems like something we should get ahead of before people
run into unknown consequences of trying their own combinations.

------
tasty_freeze
That table at the end has a column "Median Lifespan Increase
(treated/control)". No, it isn't an increase, it is a ratio.

Eg, the first entry, scenescent cell removal %135, is a 35% increase, not a
135% increase.

~~~
ekianjo
It would be good to add the base size for the observed effect in each study.

------
akuma73
Dr. Greger's talk is excellent with respect to how diet can influence
longevity.

[https://www.youtube.com/watch?v=7rNY7xKyGCQ](https://www.youtube.com/watch?v=7rNY7xKyGCQ)

------
fbr
You may enjoy Dr Rhonda Patrick's podcast as well.

[https://www.youtube.com/user/FoundMyFitness/](https://www.youtube.com/user/FoundMyFitness/)

------
Sir_Cmpwn
I know they're for illustrative purposes but I really would have appreciated
some scales on those graphs.

------
watertom
Almost all animal testing is done on animals that manufacture L-Ascorbic Acid
in their liver. L-Ascorbic Acid is an incredibly powerful hormone and
completely discounting it's presence is foolish at best and negligent at
worst.

------
antongribok
I'm a bit surprised at no mention of importance of sleep. Why is that?

Or is this because that falls outside of scope of what "longevity research" in
this case means?

~~~
beefman
Seems to me an obvious target. Soundness of sleep seems to decline
monotonically from near birth all the way to death

[https://twitter.com/clumma/status/764842049199898624](https://twitter.com/clumma/status/764842049199898624)

------
aaavl2821
if you are interested in the biopharma industry in general, in addition to the
sources she lists on her site, here is a primer i recently put together:
[http://newbio.tech/blog.html](http://newbio.tech/blog.html)

------
ThankYouByeBye
Why starve yourself by calorie restriction for 30 years when some bozo will
shoot you dead in the end .

------
659087
What's the end game here? A future ruled by 400 year old Zuckerbergs and other
multi-trillionaires?

Much of the progress in society is possible only because previous generations
eventually die off. What happens when that's no longer the case?

~~~
darpa_escapee
Hope to God that you're dead by then.

