#1

Brand new paper with many interesting insights into aging. Also some of the most extensive BioAge testing I’ve seen.
Reminds me of presentations by Peter Fedichev about nonlinear aspects of aging.

https://www.nature.com/articles/s43587-024-00692-2

Aging is a complex process associated with nearly all diseases. Understanding the molecular changes underlying aging and identifying therapeutic targets for aging-related diseases are crucial for increasing healthspan. Although many studies have explored linear changes during aging, the prevalence of aging-related diseases and mortality risk accelerates after specific time points, indicating the importance of studying nonlinear molecular changes.

The analysis revealed consistent nonlinear patterns in molecular markers of aging, with substantial dysregulation occurring at two major periods occurring at approximately 44 years and 60 years of chronological age. Distinct molecules and functional pathways associated with these periods were also identified, such as immune regulation and carbohydrate metabolism that shifted during the 60-year transition and cardiovascular disease, lipid and alcohol metabolism changes at the 40-year transition.

The observation of a nonlinear increase in the prevalence of aging-related diseases implies that the process of human aging is not a simple linear trend. Consequently, investigating the nonlinear changes in molecules will likely reveal previously unreported molecular signatures and mechanistic insights. Some studies examined the nonlinear alterations of molecules during human aging13. For instance, nonlinear changes in RNA and protein expression related to aging have been documented14,15,16. Moreover, certain DNA methylation sites have exhibited nonlinear changes in methylation intensity during aging, following a power law pattern17. Li et al.18 identified the 30s and 50s as transitional periods during women’s aging.

The cohort was followed over a span of several years (median, 1.7 years), with the longest monitoring period for a single participant reaching 6.8 years (2,471 days). Various types of omics data were collected from the participants’ biological samples, including transcriptomics, proteomics, metabolomics, cytokines, clinical laboratory tests, lipidomics, stool microbiome, skin microbiome, oral microbiome and nasal microbiome.

In total, 135,239 biological features (including 10,346 transcripts, 302 proteins, 814 metabolites, 66 cytokines, 51 clinical laboratory tests, 846 lipids, 52,460 gut microbiome taxons, 8,947 skin microbiome taxons, 8,947 oral microbiome taxons and 52,460 nasal microbiome taxons) were acquired, resulting in 246,507,456,400 data points. Overall, this extensive and longitudinal multi-omics dataset enables us to examine the molecular changes that occur during the human aging process.

Particularly noteworthy was the observation that, among all the omics data examined, metabolomics, cytokine and oral microbiome data displayed the strongest association with age.

The clinical laboratory test blood urea nitrogen, which provides important information about kidney function, is also detected in cluster 2 (Fig. 3c). This indicates that kidney function nonlinearly decreases during aging. Furthermore, the clinical laboratory test for serum/plasma glucose, a marker of type 2 diabetes (T2D), falls within cluster 2. This is consistent with and supported by many previous studies demonstrating that aging is a major risk factor for T2D28. Collectively, these findings suggest a nonlinear escalation in the risk of cardiovascular and kidney diseases and T2D with advancing age, particularly after the age of 60 years (Fig. 2c).

Our analysis revealed thousands of molecules exhibiting changing patterns throughout aging, forming distinct waves, as illustrated in Fig. 3a. Notably, we observed two prominent crests occurring around the ages of 45 and 65, respectively (Fig. 4a). Notably, too, these crests were consistent with findings from a previous study that included only proteomics data14. Specifically, crest 2 aligns with our previous trajectory clustering result, indicating a turning point at approximately 60 years of age

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Nonlinear Aging
#2

If we can guard the the disregulation from happening at age 44 and 60, then we can stop quick nonlinear aging at these 2 points in life, right?

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#3

I’m still studying the paper. The obvious question is what causes these accelerated periods of aging?

Article in mainstream media about the study:

https://www.nbcnews.com/health/aging/research-shows-ages-metabolism-undergoes-massive-rapid-changes-rcna166367

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#4

Here are the conclusions of the study.

The analysis of molecular functionality in the two distinct crests revealed the presence of several modules, indicating a nonlinear increase in the risks of various diseases (Fig. 5a). Both crest 1 and crest 2 exhibit the identification of multiple modules associated with CVD, which aligns with the aforementioned findings (Fig. 3b). Moreover, we observed an escalated dysregulation in skin and muscle functioning in both crest 1 and crest 2. Additionally, we identified a pathway linked to caffeine metabolism, indicating a noticeable alteration in caffeine metabolization not only around the age of 60 but also around the age of 40. This shift may be due to either a metabolic shift or a change in caffeine consumption. In crest 1, we also identified specific modules associated with lipid and alcohol metabolism, whereas crest 2 demonstrated prominent modules related to immune dysfunction. Furthermore, we also detected modules associated with kidney function and carbohydrate metabolism, which is consistent with our above results. These findings reinforce our previous observations regarding a decline in kidney function around the age of 60 years (Fig. 3c) while shedding light on the impact of dysregulated functional modules in both crest 1 and crest 2, suggesting nonlinear changes in disease risk and functional dysregulation.

In summary, the unique contribution of our study lies not merely in reaffirming the nonlinear nature of aging but also in the depth and breadth of the multi-omics data that we analyzed. Our study goes beyond stating that aging is nonlinear by identifying specific patterns, inflection points and potential waves in aging across multiple layers of biological data during human aging. Identifying specific clusters with distinct patterns, functional implications and disease risks enhances our understanding of the aging process. By considering the nonlinear dynamics of aging-related changes, we can gain insights into specific periods of significant changes (around age 40 and age 60) and the molecular mechanisms underlying age-related diseases, which could lead to the development of early diagnosis and prevention strategies.

The extensive level of testing (246 billion data points) is fascinating to me. It would certainly seem that we have the ability to make a reference, master-level BioAge Clock against which all new simpler, cheaper clock tests could be measured. Getting a trustworthy, effective, accurate, comprehensive BioAge Clock Test widely available at the consumer level would be a game-changer if it could show the success/failure of all interventions in humans including rapamycin, metformin, diet, exercise, sleep, statins, senolytics and all the others talked about here. Mice would become obsolete.

The ITP would turn into a circus sideshow with Richard Miller in a TopHat with a whip and the mice jumping thru flaming hoops.

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#5

Interesting new paper in Nature that suggests we age in spurts with two major aging events occuring in mid 40s and around 60 years of age.

https://www.nature.com/articles/s43587-024-00692-2

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#6

Another article about phases of aging from 2019. This one based on protein analysis.

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#8

Good Article. Proteomic clocks could be a big advance. They quote Tony Wyss-Coray in your article and he’s a founder of Teal Omics. Hopefully their proteomic clock will come out soon. Another one was just posted by @RapAdmin here:

https://mmabrasil.localizer.co/t/proteomic-aging-clock-predicts-mortality-and-risk-of-common-age-related-diseases-in-diverse-populations/15468?u=ng0rge

And here’s the paper (paywalled) by Wyss-Coray and Nir Barzilai that’s linked to from your article.

https://www.nature.com/articles/s41591-019-0673-2

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#9

Compound interest is a useful model, but why does the acceleration of aging slow down between 40 and 60? There must be multiple compounding factors involved, and we have a tolerance for poor repair up to a point, and then this wheel falls off, and then after another while that other wheel falls off. Once two wheels have fallen off, the car really starts to go bad, to mix my metaphors.

No doubt it is easier to keep the wheels on than to put them back on. Stay healthy my friends.

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#10

Maybe the body can compensate for some aspects of aging but when it can’t there’s a sudden drop in overall health and functionality. It could be related to deficiencies or overactive/underactive mechanisms. Perhaps someone taking great care in their routine can achieve an overall slower and more gradual aging than your average person.

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#11
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#12

This sort of result makes me think that measuring biological age will be very hard to do well. How can you tell which side of the slope a person is on? Probably by asking for chronological age. Funny.

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#13

In that case, starting geroprotective drugs before you enter your 40s seems like the best strategy. The body will not be destroyed and will repair itself easily. DNA and cellular damage repairs itself quickly, just like a cut hand repairs itself faster at a young age.

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#14

Probably not enough information here yet, but these charts remind me of decompensation in heart failure. While the underlying pathology is gradually getting worse, the forces of homeostasis keep functionality within pretty tight limits until the ability of homeostasis to compensate is exceeded, then the person experiences a rapid drop, or decompensation, and find themselves at lower plateau of functionality. Then they stay at that plateau through homeostasis, even though still, the pathology continues to get worse behind the scenes.

So I am curious if that sort of thing is what’s happening here… or if there truly are two big puberty-like biological events. Not simply two times where homeostasis loses its ability to compensate for gradual changes behind the scenes.

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#15

Another new article from - Science Alert.

https://www.sciencealert.com/study-finds-humans-age-faster-at-2-sharp-peaks-heres-when-to-expect-them

Using the samples from their cohort, the researchers have been tracking different kinds of biomolecules. The different molecules studied include RNA, proteins, lipids, and gut, skin, nasal, and oral microbiome taxa, for a total of 135,239 biological features.

Each participant submitted an average of 47 samples over 626 days, with the longest-serving participant submitting 367 samples. This wealth of data resulted in more than 246 billion data points, which the researchers then processed, looking for patterns in the changes.

The researchers note that their sample size is pretty small, and they tested limited biological samples, from people between the ages of 25 and 70.

“limited”???

Exactly, this is the question. If it’s a steady decline, OK, but what’s making it change speed? Hopefully, they’ve collected enough data to get some insight into that…and as I mentioned above, how to make a more accurate BioAge Clock.

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#16

This seems to coincide with general deficiencies that develop in our 40s such as Glycine, Cysteine and Taurine. It’s also when glutathione levels drop. It’s probably related.

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#17

Around 60 is when senescence is compounding and not in the good way like savings.

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#18

Taurine deficiencies increase the amount of senescent cells by a large amount. Studies have found that in mice, mice taking senolytics had more senescent cells than mice taking Taurine!

Taurine is a senomorphics that prevents senescent cells from forming and that is a key factor!

Actually I think it is the deficiency of Taurine that causes senescence.

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#19

Agreed, taurine is the true senolytic medication. Costing only 1€/g/month it is dirt cheap too.

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#20

From the topic article: The analysis revealed consistent nonlinear patterns in molecular markers of aging, with substantial dysregulation occurring at two major periods occurring at approximately 44 years and 60 years of chronological age.

The research helps me to understand why some of us on the rapamycin.news site have much better results than others with rapamycin use/dosing. It might have to do with the timing of use. I believe all people can get some improvements, but for remarkable improvements - timing in one’s starting point on the medication might be crucial to higher benefits. Use before or at the 60 years old mark.

Just as Matt Kaeberlein says in the Radiolab - “Dirty Drug in the Ice Cream Tub” podcast. If you have cancer or alzheimer’s rapamycin can help to reverse it some. However, If you start on rapamycin before you have cancer or alzheimer’s - then you won’t get them. Timing for prevention, verses how much damage has already begun… what can be repaired.

I started getting interested in my health, diet and exercise at around 58 years (losing some weight and hitting the gym 45 minutes every other day).

I plateaued in muscle gains and fat loss after 3 years… so I started TRT at age 61. Had muscle gains and some weight loss. Then a year later researched and started on rapamycin at age 62 years with almost miraculous improvements in muscle and body composition. Over the past 4 years of rapamycin dosing, my biological markers have me between 42 years and 51 years biological age. Noticeable improvements in in skin quality, muscle growth and strength, loss of visceral fat, better circulation, oral health, arthritis pain gone, inflammation reduced and memory improvement. A complete reversal of all the first noticeable aging issues that had just begun (which is what prompted me to use both TRT and then rapamycin). I was able to stop and slow the functional declines that began for me at 60-ish.

As I often have written, glad I started on rapamycin in my early 60’s wish I had started at 50!

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#21

There are many processes that increase the number of and cause senescent cells. It’s not just one thing. This list below is not complete either as it leaves a few other things that cause senescence, including one of the more important causes.

The most important cause of senescence as we age is recruitment.

Of the over 500 chemokines, cytokines, growth factors, proteases and protease Inhibitors, extracellular matrix components, and other signaling molecules, at least FOUR are known to be recruiting compounds. Senescent cells recruit nearby healthy cells to become senescent. This means that senescent cells create other senescent cells.

The Buck Institute for Research on Aging has created a data base with over 500 references. (http://www.saspatlas.com/)

Causes of Cellular Senescence

Cellular senescence is a state of permanent cell cycle arrest that cells enter in response to various stressors and damage. Senescent cells stop dividing but remain metabolically active and can influence their environment through the secretion of various factors. Here are the main causes of cellular senescence:

1. Telomere Shortening

  • Mechanism: Telomeres are repetitive nucleotide sequences at the ends of chromosomes that protect them from deterioration. Each time a cell divides, telomeres shorten. When they become critically short, the cell can no longer divide and enters a state of senescence.
  • Reference: Telomere shortening is a well-established cause of replicative senescence, particularly in somatic cells.

2. DNA Damage

  • Mechanism: DNA damage can result from various sources, including oxidative stress, radiation, and chemical exposure. Persistent DNA damage activates the DNA damage response (DDR) pathway, leading to cell cycle arrest and senescence.
  • Reference: DNA damage-induced senescence plays a crucial role in preventing the proliferation of damaged cells, which could lead to cancer.

3. Oxidative Stress

  • Mechanism: Reactive oxygen species (ROS) are byproducts of normal cellular metabolism but can cause significant damage to DNA, proteins, and lipids when present in excess. Chronic oxidative stress can induce cellular senescence.
  • Reference: Oxidative stress is a major contributor to aging and age-related diseases through the induction of cellular senescence.

4. Oncogene Activation

  • Mechanism: Oncogenes are genes that have the potential to cause cancer. When oncogenes are abnormally activated, they can induce a hyperproliferative state that leads to cellular senescence as a protective mechanism to prevent uncontrolled cell division.
  • Reference: Oncogene-induced senescence is a crucial tumor-suppressive mechanism.

5. Epigenetic Changes

  • Mechanism: Epigenetic modifications, such as DNA methylation and histone modification, can alter gene expression patterns. Age-related epigenetic changes can disrupt normal cellular functions and contribute to the onset of senescence.
  • Reference: Epigenetic changes are increasingly recognized as important contributors to cellular senescence and aging.

6. Mitochondrial Dysfunction

  • Mechanism: Mitochondria are the powerhouses of the cell, and their dysfunction can lead to increased ROS production and reduced ATP generation. Mitochondrial dysfunction is a significant factor in the induction of

  • Reference: Mitochondrial dysfunction and the resulting oxidative stress are key drivers of cellular senescence.

7. Chronic Inflammation

  • Mechanism: Chronic inflammation can cause persistent cellular stress and damage, leading to the induction of senescence. Senescent cells themselves can contribute to a pro-inflammatory environment through the senescence-associated secretory phenotype (SASP).
  • Reference: Chronic inflammation and the SASP create a feedback loop that promotes cellular senescence and tissue dysfunction.

Conclusion

Cellular senescence can be induced by various factors, including telomere shortening, DNA damage, oxidative stress, oncogene activation, epigenetic changes, mitochondrial dysfunction, and chronic inflammation. Understanding these causes is crucial for developing strategies to mitigate the negative effects of senescent cells on aging and age-related diseases.

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