Oxidative metabolism reflects our biological age, metabolic dysfunction drives frailty/aging

haidut

In several of his articles, Ray discussed the non-specific “syndrome of being sick” -i.e. looking and feeling frail, while also being at high risk for virtually any condition, but without any of the specific symptoms/signs or diagnostic biomarkers of any specific condition. Ray said that Hans Selye linked this syndrome to chronic stress exposure, which Ray said ultimately leads to severe mitochondrial dysfunction and low oxidative metabolism. The study below now presents evidence that Ray was right (again!) and that declilne in mitochondrial number and activity can be used as a reliable prognostic biomarker for future frailty and chronic diseases. In addition, the degree of mitochondrial dysfunction apparently correlates with the severity of the “sick syndrome”, so it can also be used as a diagnostic tool for how severe an already established condition is. Aside from the well-known blood tests for pyruvate/lactate ratio, acetoacetate/hydroxybutyrate ratio, GSSG/GSH ratio, etc a simple tests for exhaled CO2 using a portable capnometer could probably be a very cheap and widely available, non-invasive method for diagnosing metabolic issues and thus future disease risk. In other words, as the study itself states, mitochondrial function reflects our “biological age” and it is biological age, and not chronological age, that drives frailty, diseases and aging itself. The good news here is that, unlike chronological age, biological age can be modulated so that we experience very little to none actual aging and disease.

https://pubmed.ncbi.nlm.nih.gov/38778912/

https://uchile.cl/noticias/228185/mitochondrial-respiration-new-key-to-detecting-frailty-in-older-adult

“…A recent study published in Frontiers in Cell and Developmental Biology, titled “Decreased mitochondrial respiration associates with frailty in community-dwelling older adults” (DOI: 10.3389/fcell.2024.1301433), presents a new perspective on how to diagnose and understand frailty in older adults, based on a cellular indicator: mitochondrial respiration in peripheral blood mononuclear cells (PBMCs). This work opens a promising pathway for the early detection of this geriatric syndrome, which affects a growing proportion of the aging population. The lead author is Gianella Liabeuf, then a student in the Doctorate in Nutrition and Food (DOCNUTAL) program, and it was developed by researchers from the Institute of Nutrition and Food Technology (INTA) at the University of Chile, in collaboration with the Faculty of Chemical and Pharmaceutical Sciences, the Faculty of Medicine at the University of Chile, the University of the Americas, the Bernardo O’Higgins University, and the Interuniversity Center for Healthy Aging. “Frailty corresponds to a greater susceptibility to negative health outcomes: for example, if a frail person becomes ill, it is more likely that the illness will be severe, unlike a robust person who is more likely to experience a milder illness,” explains Roberto Bravo-Sagua, a professor at INTA, PhD in Biochemistry, and one of the study’s authors. According to the researcher, cellular metabolism can act as a reflection of that robustness or frailty. “Cellular metabolism reflects our biological age. This means that we may have a certain chronological age (years of life), but our body may have a younger or older biological age. That is, our cells may be younger if we have experienced ‘successful’ aging, or more aged if we have been affected by negative factors.” The study was conducted in 58 older adults aged 70 and above, part of the ALEXANDROS cohort (a cohort under study for over 20 years at INTA, University of Chile), and revealed that frail individuals showed significantly lower mitochondrial oxygen consumption rates (OCR), particularly in men and in those over 80 years of age. “It’s true that frailty is traditionally easy to assess and does not require complex tests. However, this study opens the possibility of obtaining a new diagnostic parameter for frailty, with the potential of gaining predictive value. That is, to detect the early stages of frailty development before it manifests clinically.”

Via: https://haidut.me/?p=2791

visalibero

@haidut

What diet would be most effective to get out of this defective state?

yerrag

@haidut

Are you referring to white blood cells when you talk about PMNs specifically neutrophils, macrophages, and eosinophils?

As rbc's as rbc's do not have mitochondria.

As PMNs use respiratory burst to create ROS to destroy pathogens, and this ability protects our body via the innate immune response which when sufficient keeps us from having to tap into our adaptive immune response, which keeps us from having to use b-lymphocytes and the use of antibodies, the use of which involves the highly stressful responses involving allergies and worse, autoimmune complications.

So, yes, I can see the benefits in having an active and highly functional innate immune system in keeping the body from aging.

eduardo-crispino

haidut's posts are automated reposts of his website content. I dont think he actually replies to individual comments here

cs3000

@yerrag good for 1st day response to a virus or clearing bacteria but innate immune system plays a major role in aging & autoimmunity (comment seems a good concept but), they stay chronically / dysfunctionally activated in common disease, e.g macrophages drive atherosclerosis , neutrophils & colitis , neutrophils & alzheimers damage too https://onlinelibrary.wiley.com/doi/10.1002/ana.25159

(i think that was a way to measure mitochondria without taking tissue samples for general idea of mitochondria function instead of them outlining that as a specific area for aging - its relevant there too though macrophages need mitochondria functioning properly to switch to an anti-inflammatory phase instead. and poor mitochondria function is 1 trigger for chronic activation of these cells damaging healthy tissue, from h2o2 leaking in excess )

yerrag

@cs3000

An excessive immune response is not to be overlooked, but I'm more focused on the ability of the immune system to respond to threats by virtue of having good metabolism.

Poor metabolic health translates to a weak innate immune response. And I think you'll agree that worrying about an excessive innate immune response is not the first thing to be concerned with. Not having a healthy innate immune system is.

cs3000

@yerrag
for infection yeah a plus having more effective killing power earlier on in the process from better metabolism. probably helps with resolving the attack response sooner which is an important focus too. i read some stuff on thyroid hormone giving animals ability to take out viruses better but maybe that was through b cells. think it worked for bacteria too through neutrophils.

about either focusing on lowering excessive innate response or ensuring healthy, i dont see the distinction it depends on what it being healthy means,
in my eyes it being healthy means it being generally less active than usual in poor health, only for short times , because its already excessively infiltrating tissues & causing extra damage where theres mitochondria dysfunction.
people with poor health that die from infections can die because of innate immune system (neutrophils damaging organs) - i think excessive innate immune response and poor health / metabolism generally go together

neutrophil - lymphocyte ratio is a common marker of poor health,
neutrophils & macrophages get by on glycolysis but lymphocytes use full oxidative phosphorylation. (macrophages use oxidative phosphorylation but it changes their response away from destruction). so maybe innate immunity is more likely to be a problem than adaptative in dysfunctional metabolism

much of disease and aging is caused by damage from immune cells (both types from innate immunity too, poor metabolic health still allows them to be powerful enough to destroy healthy cells)

healthy metabolism means less signals for infiltration so less damaging healthy tissue , and probably more early killing power & damage resolution

yerrag

@cs3000 said in Oxidative metabolism reflects our biological age, metabolic dysfunction drives frailty/aging:

neutrophil - lymphocyte ratio is a common marker of poor health,

I have this high ratio myself, yet I consider having it high, with the latest CBC showing 66% to 21%, or higher than a 3:1 ratio. But I've had this way 25 yrs ago, coinciding with the time my blood pressure started going up from the safe value of 120/80.

But I have been healthy despite the high BP, which I never (until 2 yrs ago) treated with hypertensive prescription drugs (until I had to when I developed heart failure and had to go to the ICU after my heart stopped and I had to be revived at the ER). I'm saying this because I developed heart failure not because of high BP, but because I had allowed a self-induced bronchitis to be taken for granted and the hypoxemia that was left unresolved cascaded into heart failure. I say this to emphasize that it wasn't my high BP, as left un- intervened by hypertensive drugs, that caused it.

If only to support my contention that a high neutrophil/lymphocyte ratio, in my experience, while not ideal, was something tolerable, though it definitely was associated with my high BP situation. Because during that time, I wasn't suffering from any issues. This meant zero allergies, no flu for the past 25 years (nor fever), which I would say counts for high immunity. No body aches, stomach aches nor headaches. No overweight, great sugar control, normothyroid. High endurance running, and an ability to dry fast for 3 days. Also high internal metabolism, which did not require me to work out or walk to maintain s normal weight. Which meant, despite (or because of) high BP, I was very healthy.

But I have lead toxicity, and a low grade (ie no fever) internal infection I attribute to a periodontal infection that translocated, both of which persisted and caused a continual immune response that produced a persistent level of oxidative stress. Which caused my high BP.

The high BP came from having low blood volume that my body had to increase BP to compensate for, in order to ensure the lower blood volume can still provide adequate circulation and perfusion of blood through the tissues and organs without fail.

The low blood volume resulted from lower serum albumin, which was lower from its being used daily as an extracellular antioxidant to counter the oxidative stress arising from spillover ROS resulting from the immune system creating ROS to kill pathogenic microbes that was never totally eliminated, as well as the oxidative stress from the lead toxicity that never got resolved as well.

But I could not say my immune system was overactive and dysfunctional. It did what it had to do to protect me from lead toxicity and periodontal infection that needed more external intervention (heavy metal chelation and use of better methods of infection control other than pharma antibiotics) in order to eliminate.

Through it all, I had high BP which did not cause my health to deteriorate (I feel high BP was a protective adaptation though our doctors would say otherwise), and the albumin that was constantly being used up and lost, was a renewable resource in the sense that the liver kept producing more of it to replace the ones used. In this way, my body was kept from suffering any tissue destruction that may have resulted from the constant oxidative stress from heavy metal toxicity and spillover ROS my immune system generates. My tissues and organs are protected and intact.

So, I guess, what would be portrayed by mainstream medicine as dysfunctional isnt really so. And what really is dysfunctional could just be the response of medicine to try to intervene when it shouldn't. In all the ways modern medicine could.