The quest for immortality. =========================== Venki Ramakrishnans new book ''Why we die''. The science of ageing and the quest for immortality is a great read. With - along the way - many great insights into the actual biochemical wonders of life. --- In ''Blue zones'' (Longevity areas), regions, where people live measurably longer and healthier lives than the global average, it has been noticed there is tendency towards: - Diet: A largely plant-based diet, often with limited meat consumption. - Physical Activity: Daily physical activity is integrated into daily life. - Social Connections: Strong social networks and a sense of belonging. - Purpose and Meaning: Having a sense of purpose in life. - Stress Reduction: Communities often have practices and cultural norms that promote stress reduction. On livingto100 you can see how you are doing yourself. Still, lifestyle is probably not the controversial part, when it comes to ageing and longevity. Probably, the real controversy has more to do with whether there is, or will ever be, a pill out there, that people can take, which will give a significant rise in lifespans… - - - Venki Ramakrishnan starts out by noticing: Unlike cars, which consists of mechanical components that we can swap out for new ones, as they wear out, we cannot simply replace ourselves with new parts and keep going indefinitely. P. 30. Indeed, life is not a simple thing, with big, uncomplicated, parts, where it is easy to see where parts ends and others begin. Instead, life is more like small fragile things, with small, fragile parts, that are all intertwined… Venki Ramakrishnan writes: Life might have begun in a primordial world in which RNA carried out chemical reactions, as well as stored genetic information. As life evolved to become more complex, using an unstable molecule to store an increasingly large genome was not viable. And so the more stable DNA was used to store genetic information. P. 62. Still, DNA damage can still occur. When a cell senses significant DNA damage, it triggers a DNA damage control. Sometimes the cell will go into senescence, a state in which it is unable to divide any further. Sometimes the cell is triggered to commit suicide. P. 66. I.e. there are many, pretty complicated, mechanisms that help keep our cells healthy - and up and going. In DNA damage control, mechanism like p53, a tumor suppressor protein, become helpful. I.e. in response to cellular stress like DNA damage or oncogene activation, p53 can trigger apoptosis, effectively eliminating damaged or cancerous cell. Still, even healthy cells can only go on for so long. See the Hayflick limit: The Hayflick limit, also known as the Hayflick phenomenon, refers to the phenomenon where normal human cells, when grown in a laboratory setting, can only divide a certain number of times (typically 40-60) before they stop dividing and enter a state of senescence (cellular aging) or cell death. Lots of things need to be “just right” in order for the cellular mechanisms to go on with the right cell divisions, and so on. See e.g. telomerase: Telomerase is a reverse transcriptase enzyme that adds DNA sequences (telomeres) to the ends of chromosomes, preventing them from shortening during cell division. It is crucial for maintaining genomic stability and is found in high levels in stem cells and cancer cells. Venki Ramakrishnan writes: People with defective telomerase, or have less than normal amount of it, prematurely develop a number of diseases associated with old age. Likewise a stressful like can often make us appear to age faster. Stress has multiple effects on our physiology, and how exactly it affects the aging process is complex. But one of the things it does is to accelerate telomere shortening. When we are stressed , our body produces much more cortisol. Referred to as the stress hormone, which reduces telomerase activity. P. 77. Certainly, Venki Ramakrishnan does a good job, in the book, of introducing us to these mechanisms, and gives us many details, without getting lost in these same details… In the complex world of biochemistry DNA isn't present as a naked molecule. Rather it is heavily coated with proteins called histones. And this mixture of of proteins and DNA is called chromatin. P. 95. Tags on histones can act as a signal for the cell to recruit other proteins to the region, and either inactivate chromatin, or open it up (acting as epigenetic marks). Giving us 2 processes. DNA methylation usually silences a gene, while histone acetylation signal that the gene is to be actively transcribed. P. 96. Sometimes things goes wrong inside the cell mechanisms. Here a molecular machine called the proteasome becomes important, as it works as a giant garbage disposal machine. P.110. Proteasome activity declines with age. And we gave reason to believe it is a cause of aging. Deliberately introducing defects in the proteasome or the ubiquitin tagging machinery can be lethal. And even minor defects can lead to diseases associated with old age, such as Alzheimer's and Parkinson's. P. 110. Not only are the individual parts in the “life machinery” pretty complex, they also need to be started at just the right time. Starvation, a viral infection or too many unfolded proteins can trigger a unified mechanism to deal with such stress at the cellular level level. ISR - The integrated stress response - to the rescue. Which, of course, should only be initiated in certain very specific situations. It is no good to suppress all protein generation, and it is not good to suppress too much. P. 115. It is all a matter of balance. Take Alzheimer’s disease: The immediate cause might be might be the formation of tau or amyloid - beta filaments in the brain. However, an earlier and root cause is the cells inability to manage the excess of unfolded proteins that aggregate to form filaments in the first place. This in turn is caused by damage to the control system. The quality control an recycling mechinery of the cell. Where, often, we find that damage to the control system is the result of aging P. 122. All difficult to treat, like cancer, because it is our own cells that have gone out of control. P 123 To keep the whole cellular machinery going we need energy. Which our cells mitochondria should give us. According to Venki Ramakrishnan: Mitochondria are not just energy factories in the cells. But are also intimate involved in the cells metabolism. If the acquire defects with age, they contribute to the decline of the cell they inhabit and speed up aging. P. 178. Defective mitochondria are more prone to rupture and can leak their DNA and other molecules into the cytoplasm of the cell. The cell might mistake this for bacterial invasion, triggering inflammation. Our neurons, which are either very long lived, or do not regenerate at all, are particular prone to aging mitochondria. It may be one reason that our cognitive abilities decline. Neurons with aging mitochondria are also less able to use the recycling pathways to clear away defective proteins. As a result we become more prone to dementia with age... P. 178. Any defects mitochondria acquire with age set of a whole sequence of events that themselves accelerate aging. All of these affect the aging of individual cells. P. 181. Still, sure, people do not want to age (and try what they can to stay young…)... Entrepreneur Bryan Johnson tracks 33,537 biomarkers, takes 111 pills a day, and has a team of 30+ doctors monitoring his body. Indeed: What would it look like to treat the human body like a startup? By now it should not be surprising that Venki Ramakrishnan is a bit skeptical … Peter Thiel, Sam Altman and other Silicon Valley billionaires have signed up to be cryogenically preserved after they die (in order to be brought back to life in the future) or have signed up for brain back-up procedures — memories and all — storing it forever. Unsurprisingly, Elon Musk is also onboard when it comes to cryonics. Certainly, there should be a Cryonics facility on Mars, ''We should die on Mars, just not on impact''. Again, Venki Ramakrishnan is a bit skeptical. And notices that without body, the brain might not be able to make much sense of the world. The brain has relation with the rest of the body. Basic needs comes from the body. Hunger, thirst etc. A brain without a body isnt really a human brain… - - - And, even if it might be possible to slow down certain ageing processes, Ramakrishnan appears to be quite adamant that it doesn't make much sense to hope for an actual, completely, younger body. In Ramakrisnans words: It is not possible to grow younger. Since that would require the impossible feat of replacing all of the cells and tissues with new ones. Replacing and reprogramming the brain is more the subject of science fiction than likely science fact . P. 208. About the pill that we can all just take to stop ageing, he writes: There are more than 700 biotech companies. Focused on aging and longevity. Some of these companies have been around for decades but have yet to produce a single product. P. 309. Well, well. Realism is, of course, a good thing. Still being a kill joy is no fun either… And who knows, some pills might still might end up being helpful. If not in giving you decades of extra life, then perhaps a few years… Which also could be worthwhile. Still, a great book by Venki Ramakrishnan. A truly fascinating introduction to the exciting years ahead when it comes ageing and longevity. ---- Simon Laub. July 14th, 2025.