大脑老化问题，Peter Fedichev

[RapAdmin]

朋友们，让我展示一下可能是世界上最恐怖的视觉效果。虽然数据和曲线的来源存在问题，但关键要点在不同数据集之间保持一致。令人痛苦的是，显而易见的是，许多与智力相关的特征早在慢性疾病随着年龄的增长而出现之前就开始下降。

这种终生的逐渐衰退在所谓的“流体智力”中尤其明显。这是指我们学习新信息、适应新情况和解决以前从未遇到过的问题的能力。

相比之下，我们“结晶”智力的某些方面——比如我们的语言和算术能力，这些能力是我们一生中磨练出来的——一旦在生命早期掌握，就基本上不会随着年龄的增长而改变。

以下是我从这次观察中得出的见解：

智力不是线性的。如果我们要绘制出这些特征，我们将至少识别出两个不同的类别。第一个与结晶智力有关，包括语言掌握和数字技能。第二个与流体智力相一致，代表我们许多人传统上认为的智力，通常使用智商量表或 g 因子等工具进行测量。

智力的双重性表明，至少在人类中，与最重要的认知功能相比，语言和基本算术的能力是由不同的系统控制的。

我们清晰而不是优雅地沟通的能力源于不同的认知功能。随着年龄的增长和神经元的丧失，优雅沟通的能力比清晰准确表达的能力持续得更久。警惕雄辩的演讲者，因为有时，雄辩掩盖了实质内容的缺乏。

可以想象，像 ChatGPT 这样的大型语言模型 (LLM) 仅模拟这些系统之一，很可能是结晶智能。然而，我认为流体智力是人类智力的本质，它很可能独立运作。支持这一观点的是，尽管现代法学硕士的语言能力很强，但他们的智商分数仍然出人意料地温和，在 83 到 150 之间。但像我这样尝试用 ChatGPT 给孩子做作业和做一些实际工作的人不会相信 150。

这并不意味着他们缺乏潜力。 OpenAI 最具创新性的策略之一是通过人类交互来训练语言模型，使模型能够学习和进化。鉴于人类同时拥有结晶智能和流体智能，机器有可能通过与我们的互动来协同发展。

这表明这些机器的最佳状态尚未到来。然而，对我们来说，情况更加发人深省。随着年龄的增长，我们的认知状况开始类似于法学硕士的认知状况。从隐喻意义上讲，法学硕士是我们在时间的摧残后所留下的智力成果。

Carthāgō dēlenda est，迦太基必须被摧毁，因此衰老必须被停止，男孩和女孩

一如既往，如果你喜欢在这里看到的内容 - 关注我，点赞并分享 - 我需要你的朋友。谢谢。

彼得·费迪切夫，
来源： https ://twitter.com/fedichev/status/1694980930501222549?s=20
Peter 的公司是“Gero”，更多信息：关于 Gero

相关阅读：

大脑衰老生物标志物框架：衰老生物标志物联盟的共识声明

开放获取论文： 大脑衰老生物标志物框架：衰老生物标志物联盟的共识声明 |生命医学|牛津学术

lnad017.pdf (380.9 KB)

[arugula]

@RapAdmin

the key takeaway remains consistent across different datasets.

I doubt this is true for people in particular professions. I know of people in my department in their 80s who are still publishing original (and valuable) works. They tend to be beanpoles who eat their vegetables, though.

[desertshores]

“In contrast, aspects of our “crystallized” intelligence – such as our verbal and arithmetic abilities, which are honed over our lifetime – once mastered early in life, remain largely untouched by age.”

I don’t necessarily agree with this. I now have to use a calculator for problems I could once do in my head.

I like the chart at the top. I think it is fairly accurate. My perceptual speed, which I define as being able to find things among the clutter, has suffered, and spatial orientation, which I define as something like waking up suddenly and wondering where I am. It takes me longer to orient myself if I leave a building through a different door than when I entered.

[RapAdmin]

What we need is a well-funded clinical trial program (think Impetus Grants or Hevolution Foundation) to create a testing program similar to the “million molecule challenge” for aging, but for brain aging.

And perhaps a phone app for testing fluid intelligence, while tracking supplements and drugs you are taking - so we can gather real world experience faster from all the biohackers and health enthusiasts out there - to see what is working today at mitigating this issue.

I suspect rapamycin helps mitigate these issues Peter cites, but we need data.

Get your Impetus Grant applications in by September 15!

Guide for writing Impetus applications [2023] — Longevity Impetus Grants

Apply — Longevity Impetus Grants

[desertshores]

Personally, I have a stronger inclination towards addressing the markers of brain aging as opposed to those of body aging. After all Stephen Hawking never seemed particularly distressed in his ravaged body.

[RapAdmin]

I agree - and while slowing aging of the brain, and the body, are not mutually exclusive, I also would put a much higher priority on my brain than my body.

I’ve not done a ton of research on the topic - but it seems like there should be an ITP like organization that is focused exclusively on slowing brain aging.

[RapAdmin]

And related to this topic more broadly… this news came out today:

UK Biobank Dementia Risk Score outperforms other widely used scores

Dementia risk study finds 11 key factors behind condition

I had never heard of the “Townsend deprivation index”, so I looked it up… its a measure of poverty.

Townsend deprivation index

Full Paper (open access/download) Here: Development and validation of a dementia risk score in the UK Biobank and Whitehall II cohorts | BMJ Mental Health

[Bettywhitetest]

Inoculation against viral and bacterial infections could be one of the most important aspects to protect against brain aging. I was a bit cavalier about catching colds/flu when working at a college and its contagious students. But catching even a common cold may have a very defined impact on brain health - particularly at middle age. Recent research
The Impact of Routine Vaccinations on Alzheimer’s Disease Risk in Persons 65 Years and Older: A Claims-Based Cohort Study using Propensity Score Matching - IOS Press looks at common vaccines and puts forth even the type of most effective ones - “We also hypothesize that recombinant (when compared with live attenuated) and conjugated (when compared with unconjugated) vaccinations are associated with a greater decrease in AD risk due to the greater protection against infectious disease from Shingrix (compared to Zostavax) and the more robust adaptive immune response induced by conjugatedvaccines.”

I would guess given the pace of new research, an inoculate could be targeted towards brain aging soon. This is a shift from what drug companies have tried spending billions on ineffective prevention or cures.

[Joseph_Lavelle]

I would argue that brain health and body health are the same thing. I am not an expert, but the more I learn about metabolic health, the more I see the impact it has on the brain. Attia was saying “type 3 diabetes” for a long time. And, now I see that Advanced Glycation End-products (which come from metabolic ill health & diet) are believed to damage the brain in addition to the many negative effects on the other parts of the body (eyes, skin, tendons, blood vessels, kidneys, etc.). Of course we should address symptoms with targeted interventions when necessary, but solving root causes provides broad relief (or at least slowing the rate of damage) to brain and body. And just as we need to be physically active to have a “healthy” body, our brain “skills” need to be exercised as well. Conscious brain skills (thinking, remembering, etc.) and unconscious brain skills (coordination, balance, etc.) are subject to the “use it or lose it” rule just like everything else. I just recorded an interview with the author of Physical Intelligence, Dr. Scott Grafton, so I full of brain talk right now.

[John_Hemming]

I agree with that, but also it is interesting how the drop in blood pressure with sleep causes CSF with a high concentration of melatonin to wash the brain cells. Ideally we older people would improve pineal function to do this. However, chugging melatonin to do this via both serum and CSF i think works although i cannot confirm the route, both may work.

[desertshores]

I hope so. I am now “chugging” 100 mg+ per night. As I previously said: I am surprised that it doesn’t cause me any daytime sleepiness.

[John_Hemming]

Sadly i have no measurements on cognitive function. I did think monacolin K caused memory problems so i stopped it and i believe things improved.

There are things i know melatonin does, if you suck it then it reduces gingivitis. I think it also reduces body odour. ( a ros effect)

The general reduction in oxidative stress is good.

[jakexb]

Well this sucks.

I’ve seen this in my parents as they’ve hit the far right section of that chart. They’re not experiencing dementia, but things that require any amount of “figuring out” are just instantly too frustrating now and they become irritated and give up.

[RapAdmin]

Take care of your vision…

More Evidence Linking Impaired Vision and Dementia Risk

and

Diversity in Daily Activities Might Slow Cognitive Decline

[jakexb]

Would be great to see a similar chart following the different types of cognition when treated with PF4 which is, at least by some definition, de-aging brains by decades (in human terms). Probably very difficult to measure different aspects of congnition in mice when they might not even really have all of these types to begin with?

[Bettywhitetest]

Related to the topic, the following showed up in my inbox this morning…

Improving memory with transcranial neuromodulation

[Jonas]

@desertshores

. I am now “chugging” 100 mg+ per night.

How long has you been doing this and what made your decided on the dose? what are the net impact on your sleep and brain health?

[LaraPo]

100 mg of melatonin per night? How many hours do you usually sleep? 3 mg make me very sleepy. I remember reading somewhere (don’t remember where ) that too much of melatonin has the opposite reaction and would contribute to sleepless nights. Do you sleep well?

[desertshores]

Put “melatonin” in the search bar at the top of this thread and read John Hemmings’s comments.

Surprisingly mega-doses of melatonin have not had any effect on my sleep and cause me no daytime sleepiness. Subjectively I have felt zero effects.

I am mainly taking melatonin for its anti-cancer properties, though it has a host of other geroprotective properties. The anti-cancer property is dose-dependent. I am still looking in the literature to find the optimal dose, but the anti-cancer properties seem to start at >20mg/day.

I have been taking a dose up to 20mg nightly since the 1980s.

After reading John Hemming’s posts about taking ~100mg+ nightly, I decided to up my dose.

So far, John Hemming is still ticking and so am I.

I will report if I have any ill effects from taking very high doses.

Among the leading causes of death in the elderly are heart disease, cancer, cerebrovascular diseases, and Alzheimer’s disease.

“It was reported that melatonin may regulate the activation of T/B cells in pinealectomy mice in a dose-dependent manner [40]. Besides, it shows immunomodulation and neuroprotective potential in a pharmacological Alzheimer’s disease mouse model”

“The role of melatonin in cancer treatment and prevention have been widely studied and numerous experimental studies proved the anticancer effect of melatonin against many cancers, including colorectal, breast, gastric, prostate. ovarian, lung, and oral. The anticancer effect of melatonin is mediated by integrated mechanisms, such as apoptosis induction, immune system modulation, targeting cancer altered mechanism, angiogenesis inhibition, and antimetastatic effect.”

A good general purpose about the properties of melatonin:

Melatonin in Cancer Treatment: Current Knowledge and Future Opportunities

[desertshores]

A few weeks after I started taking rapamycin my sleep greatly improved and I was able to reduce my nightly sleep stack.

Oddly, only because others report otherwise, I have noticed no correlation between melatonin dose and daytime sleepiness. The regimen I am on; diets, rapamycin, supplements, etc. causes me no daytime sleepiness. I did notice that I was no longer sleepy in the afternoons after I started rapamycin.