yana-notes

Longevity

2021-11-22 reference:

Longevity #

Bit of a MOC.

Alex Chen #

  • https://www.pinterest.com/inquilinekea/biochemistry-of-aging/ pretty pictures!
  • He’s on FIVE episopdes of Simulation. Incredibly lucid and holistic thoughts on so many topics.
    • Simulation #184 Alex K. Chen - Interesting Things Happen Around Alex
      • Encyclopedic learning is opposed to the domain of social media, which is needed for being a true generalist
      • It’s important to stay in touch with your colleagues, because people lose track of the input history of the abstractions they’ve learned (i.e. in your formative years) and the possibly idiosyncratic ways you’ve learned it.
  • https://twitter.com/InquilineKea/status/1717965503619371210
    • Sparsity is “making more with less”. Sparse sensor placement. This is why you go after the hubs, and take greatest care to preserve their integrity (just as integrity of higher-order thalamic nuclei is most important thing)
    • Oh yeah and Andrej Karpathy is the ideal exemplar of a form of low-nonsense/low-noise/low-pollution compute. One not distracted by Romeo Stevens’ babblers (babblers LIKE the NYT, LIKE the stock market) - his actions are INVARIANT to this. That’s why I keep mentioning him….

Laura Deming #

Alex Chen thinks she’s the most unschooled person in the whole space.

  • Tips for newcomers to longevity biotech
    • Build mental models of how we manipulate human biology, on the molecular level.
  • https://www.ldeming.com/how-to-help
    • Learn basic biology: read Alberts, Join an iGEM team and hone your experimental skills.
      • International Genetically Engineered Machine - This is an annual synthetic biology competition. Initially aimed at undergrads but has branched out the demographic a bit
    • Learn how the industy works: Subscribe to FierceBiotech and LifeSciVC, and read Peter Kolchinsky’s writing. Read ‘The Billion Dollar Molecule’ and ‘The Antidote’ by Barry Werth, as well as ‘Genentech: The Beginnings of Biotech’ by Sally Smith Hughes.
      • Kolchinsky’s writing in question (linked) = The Entrepreneur’s Guide to a Biotech Startup
    • Join a lab/company.
      • I’d recommend building a portfolio of work by doing basic analyses on public datasets. Check out 1000 Genomes, GEO, or LINCS. Look at papers that use those databases, download a small portion of the data, and start playing around with some basic models. Even if you only reproduce an already published model, the act of working with sequencing data or molecular structures is a good start.
        • LINCS: The Library of Integrated Network-Based Cellular Signatures (LINCS) Program aims to create a network-based understanding of biology by cataloging changes in gene expression and other cellular processes that occur when cells are exposed to a variety of perturbing agents.
  • https://www.ldeming.com/longevityfaq
  • https://ldeming.posthaven.com/understanding-biology-quickly
    • The closest I’ve come to a satisfying answer is to form mental models of the underlying concepts that are robust, manipulatable, and with which you can run thought experiments. This isn’t a necessary or sufficient condition for deep biological understanding, but it’s one of the few things you can do outside of a lab and check.
    • People whose thoughts I admire often say that they ‘don’t understand something’, despite a perfect ability to recite the textbook examples of it.
    • She loves http://book.bionumbers.org/, Bialek’s Biophysics: Searching for Principles, https://pdb101.rcsb.org/sci-art/goodsell-gallery, and Principles of Physical Biology.
  • https://ldeming.posthaven.com/advice-for-ambitious-teenagers
    • Question everything Isaac Newton’s Cambridge notebooks from his Annus Mirabilis and age 21-23 are excellent in this regard. He has a page (list of topics here) with very silly sounding questions. He is 21, alone in his college dormitory, and obsessively covering notebooks with questions like ‘what is heat?’, ‘why do things stick together?’, ‘what is light?’.
      • Grothendiek (one of the most famous and influential mathematicians of the 20th century) famously became completely confused in college by what a teacher meant by ‘volume’. This is a simple concept everyone learns in high school. Grothendiek was completely confused by the explanation most high school students accept as rote. He subsequently made some of the most important mathematical advances in the 20th century. Learn to be very skeptical when everyone talks about something as though it is obvious - few things in science are, at their core.
    • Build something excellent: pick one project to work on for at least one year.
      • If you want to work on something which requires a biology or chemistry lab, it may take ~6 months. Be persistent. Email every scientist you can find with a concise note describing your interest in their research, and you may find one who will help you. Do whatever it takes to get to the lab
    • The best people, teenagers or not, are somewhat embarrassed by anything successful that they do, and immediately refocus on the next goal out of a desire to not think about the achievements of the past. Be that person.
  • Laura Deming: Self-Education and the State of Longevity
    • “I would not start in the field of aging first - that is the worst possible place to start. it took me a very long time to like reverse all the damage that that did.”
    • Alex Chen comments: if you google “biophysics of aging” you get practically nothing". There like, needs to be a better guide to learn biophysics/physical cell biology that’s more motivated by information-theoretic/complex systems level OR single-unit-cell-interaction level… There’s a sense in which pretty much MOST of the ways that people enter the field of aging come from highly suboptimal routes that don’t explore the first principles (you can major in physics first, but even physics is often taught in a highly substandard fashion - even Laura herself majored in physics and didn’t seem to like it very much and it seems like the better way is to ask ALL the questions yourself and come up with all the first principles from these questions and then learn from there)
      • … As number of aging papers increases, this still doesn’t mean we have a better understanding of the MECHANICS or narrative (the field “explodes” in number of papers if not insight). There are still some people who summarize the field BETTER the more high-N papers come out (simply b/c they are fast readers and always somehow pick out JUST the right quotes to fetch out even if they don’t read the entire book (I’ve noticed that Laura often mentions on twitter that she’s skeptical of the optimal path towards reading books OR papers - like not reading them cover-by-cover). It’s clear and obvious that Laura is SUPER-unschooled (not many have the confidence OR courage to unschool themselves as aggressively as she or michael faraday ever did) and HAS to do everything her own way (define things her own way) in the face of constant social pressure to the contrary (even the helpful kind of social pressure), and that maybe a better way of learning would be to define all your questions/what you have difficulty on and then get others/the Internet to help fill you in on what you’re weak on (even some of the questions she asks on twitter are surprisingly basic, but important despite being basic and something you’d think you would have learned in a physics education but didn’t - I face a similar issue). Evidently she is starting too dominate the narrative around aging, whicch kind of shows the lack of resourcefulness/imaginattion of everyone before her (though she also stands on the shoulders of THESE giants!)

Life #

Hallmarks of Aging #

https://www.lifespan.io/road-maps/the-rejuvenation-roadmap/

  • Genomic instability
  • Telomere attrition
  • Epigenetic alteration
    • Loss of epigenetic information as a cause of mammalian aging (Jan 12 2023) from Sinclair’s lab.
      • the act of faithful DNA repair advances aging at physiological, cognitive, and molecular levels, including erosion of the epigenetic landscape, cellular exdifferentiation, senescence, and advancement of the DNA methylation clock, which can be reversed by OSK-mediated rejuvenation.
        • OSK = the delivery of 3 Yamanaka genes Oct4, Sox2, Klf4. (The other Yamanaka factors are Oct3 and c-Myc.)
  • Loss of proteostasis
  • Deregulated nutrient sensing
  • Mitochondrial dysfunction
  • Cellular senescence
  • Stem cell exhaustion
  • Altered intracellular communication

Puberty #

Backlinks

Interactive Graph