Slowing Aging One Organ At A Time (Bill Haseltine)

#1

Aging seems to happen to the whole body at once. Hair turns gray, skin wrinkles, muscles weaken and memory fades. Recent epigenetic studies reveal that not all organs age at the same rate. Some tissues can age faster or slower than others.

Traditionally, most efforts to combat aging have focused on interventions that slow aging throughout the body. This study highlights a different approach. It asks if organs age at the same rate. The study focuses on modification rates across different organs and the ways these might be altered. This suggests there may be ways to change organ age without affecting the rest of the body. Targeting specific organs may extend healthy life by reducing the burden of aging in a crucial system.

Turning The Right Genes Up Or Down

DNA is the same in almost all cells, and they offer a wide range of variations and models. The body does not build every model at once. Cells use helper proteins, called gene regulators, to choose which model to build and which pages of the instruction book to ignore.

Building on this understanding of gene regulation, a recent study systematically screened approximately 200 transcription factors. These are special proteins that act like switches, turning genes on or off. The study screened these proteins to identify those capable of rejuvenating aged cells. It used fibroblasts, which are common cells found in connective tissue, such as skin. Aging was simulated in the lab. By comparing gene expression in aged and young fibroblasts, the study identified specific transcription factors whose activity changed with age.

To precisely control gene activity, the study used CRISPR-based gene modulation. This technology can increase or decrease the activity of specific genes. For this research, each transcription factor was tested individually in aged fibroblasts. More than a dozen of these changes improved how the cells functioned, restoring youthful patterns of gene activity, boosting their ability to handle stress and increasing their growth rate. These improvements were observed while maintaining their original identity as fibroblasts.

Making Old Livers Act Younger

The liver showed the most improvement. The liver processes nutrients, metabolizes drugs and chemicals, and removes them. It also stores and releases energy, and produces hormones for metabolism and immunity. Aging in the liver leads to more fat accumulation, fibrosis and impaired metabolic function. These changes contribute to fatty liver disease and problems with sugar metabolism. Maintaining a younger, healthier liver can significantly affect healthspan and longevity.

This study focused on CCAAT/enhancer-binding protein beta (C/EBPβ), a transcription factor that plays a central role in regulating metabolic processes and detoxification in liver cells. Under normal conditions, it helps maintain proper breakdown and storage of fats. It also supports glucose metabolism and enables the liver to respond to metabolic stress. With aging, both the levels and activity of the protein decline. This contributes to fat buildup, increased fibrosis and impaired liver detoxification.

Read the full article: Slowing Aging One Organ At A Time (Bill Haseltine)

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#2

Yes, this is more about normalizing lifespan and increasing healthspan than purely extending the natural lifespan. Look at the approach of fixing the weakest links, whatever they may be - a more focused approach would be to zero in on the actual weakest link, which involves first identifying it - not an easy task. Otherwise this makes little sense. Imagine that your weakest link is AF resulting in fatal cardiac arrest. But your tools allow you to optimize liver health. Guess what - you’ll die right on schedule from the AF, the only difference would be you die at exactly the same time, but with a healthier liver, which by the way was already healthy enough (since it was not one of your weakest links).

So what does this approach bring to the table? At best, it can give us tools to fix the weakest links - but only if we can identify those weakest links in the first place, otherwise this is a kind of a nothingburger that might at best slightly better your healthspan.

Of course, access to better tools is always good. This still is not as good as making progress with the Holy Grail of a global slowing of the aging rate. But we’ll take what we can get. Meanwhile, even achieving the Holy Grail, is only a benefit if you can fix your weakest link - because a bum ticker will zero you out tragically early, even if your corpse shows a remarkably young profile everywhere else.

This is why I remain unmoved by all the complaints about how medication “X” is not a longevity agent. For example, statins are not “longevity” drugs, having failed all max life extension trials in animal models. But so what? If they save you from premature death from your weakest link, then it allows you to take full advantage of your proper longevity drugs, such as (hopefully) rapamycin. But all the rapamycin in the world will do you no good if you croak from your CVD weakest link, and that’s where statins come in.

Therefore I continue to be an evangelist for doing all you can to identify your specific individual weakest link(s) - and FIXING them - by any means necessary, including a polypharmacy of drugs none of which are longevity drugs by themselves - here I like @cl-user approach. What I would love for him to do, would be to try to identify the critical pathways that limit your lifespan in the first (earliest) point of failure. This is of course extremely difficult, because you may simply not be able to uncover what it is that is your weakest link because you are not specifically looking for it. That’s a limitation. In fact, otherwise, @cl-user 's approach mirrors the OP approach, a generalized healthspan bettering, without a guaranteed lifespan expansion if you don’t happen to come across - and fix - your weakest link, the one that will strike you dead first. Everything else is fiddling at the margins.

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#3

Or what if we can adress many parts of the body with different approaches in ways on top of and beyond what we can just do with generic methods and so pull the whole organism up?

Or what if even things are not yet the first thing that will kill joy are still having negative side effects on other things that will?

#4

Keep in mind something that I believe Brian Kennedy (or somebody else - my memory may be faulty) said - if an organ starts working better, then that translates into better functioning of the whole organism (within limits). So there may be good reasons for optimizing health of individual organs as a general principle, hoping for a more global effect.

As I stated earlier - what you really want to identify are ways of optimizng pathways and not just fixing downstream effects of faulty mechanisms. Because for example you may have a drug that eliminates some symptom of a pathology in an organ, but all that does is prevent immediate effects. What you really want, is to fix the upstream pathway that caused the downstream pathology in the first place, that way you get a more generalized benefit. The analogy here might be the use of anti-coagulants that lower the odds of a stroke, because they make clots less likely. But that does nothing to fix the underlying problem of atherosclerosis and the subsequent formation of clots. The anti-coagulants might lower the odds of getting a stroke, but do nothing to fix all the other problems that flow from the presence of atherosclerosis. Instead, you want to prevent atherosclerosis in the first place, and that way you won’t have to worry about ischemic clots/strokes. At that point you don’t need or want anti-coagulants (which btw. do nothing for the other kinds of hemorrhagic strokes), because you’ve taken the whole issue off the table. So if you are addressing your vascular system through interventions, you may want to focus on the pathway that will give the most comprehensive benefits (generally the most upstream). That’s why I like @cl-user 's approach of focusing on pathways in looking at which drugs affect it by MOA. This allows for a more upstream and more global effects. And of course we all have our individual substandard or faulty pathways that we should address - and after super in-depth mapping out of all kinds of pathways, I bet @cl-user can create a hierarchy of pathways to address in a cascade starting from most urgent first, which will be different for different people. I’m not sure the AI or databases are there yet, but this is the future direction. Global effect of slowing the rate of aging on the one hand and finding and fixing faulty pathways on the other.

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#5

That’s a very good explanation of what I’m trying to do.

For instance for me the most most urgent pathways to fix are those:

  1. very-high CAD risk from homozygous PCSK9 gain-of-function plus 9p21 double heterozygous plus MYLIP/IDOL homozygous;
  2. beta-cell secretion deficit on a paradoxically insulin-sensitive background;
  3. a keystone NRF2 / glutathione bottleneck confirmed across at least six reports;
  4. distributed methylation pressure ;
  5. elevated IGF-1 production tendency partially counter-balanced by one copy of the FOXO3 longevity haplotype;
  6. homozygous PTPN22 R620W autoimmunity risk (mitigated by absent HLA counterweights);
  7. NO-signaling convergence (GUCY1A3 + NOS3 + PDE5A + SPR);

For instance if I don’t fix #1, my life expectancy will be rather reduced. As the mutations cause a gain of function of the PCSK9, the fix is pretty easy: Repatha which is a PCSk9 antibody.
Before doing those reports I was on rosuvastatin + ezetimibe + bempedoic acid. That sort of worked but treating the symptoms rather than the fundamental cause.

#7 is similarly easy to fix with tadalafil + l-citrulline. I that case also it will fix the exact cause rather than just the symptoms.

#2 is much more tricky. I spent years trying to understand why I have glucose regulation issue while I’m extremely insulin sensitive (HOMA-IR 0.6). The answer is genetic beta-cell secretion deficit + other related issues. There Is no exact fix for that but imeglimin will partially help an I’m currently trying that.

Finally, pathway #3 (NRF2 / glutathione bottleneck) was unexpected and silent, as it does not map to easily identifiable symptoms despite impacting multiple organs and functions across six reports.