Inflammation as a biomarker of successful aging — evidence in semi-supercentenarians
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Inflammation is a critical element of the immune response and occurs when the body is exposed to harmful stimuli, such as pathogens, damaged cells, or irritants. Some scientific evidence indicates that centenarians, those who live to 100 years of age, have lower biomarkers of inflammation. Long-lived people eventually develop age-related diseases – just later in life. The onset of these inflammatory diseases may occur when genetic programs which have given them an advantage begin to falter. In this clip, Dr. Valter Longo describes how a fasting-mimicking diet can reduce markers of inflammation, such as C-reactive protein and Interleukin-6, possibly by killing damaged cells and regenerating others and resetting the system back to a more youthful state.
Rhonda: The other thing I thought about that was very interesting, and I'm not sure if you've...you've probably read this paper, but it came out of Japan a few months ago, I don't remember the group, but they were looking at a variety of different biomarkers in the elderly population, in centenarians, in semi-supercentenarians, and in supercentenarians. And they looked at all sorts of biomarkers that are related to aging, so it looked at telomere length, they looked at senescence, immunosenescence, they looked at all sorts of inflammatory biomarkers. They looked at metabolic markers, glucose regularly, you know, insulin sensitivity, they looked at kidney function, you know, the whole pack, just tons of different biomarkers.
And they were trying to find which biomarkers were consistent with healthy aging in all populations. So, not just, you know, to make it to centenarians, but to make it to every single age group. And what was identified was the only biomarker that was consistent with all the age groups was inflammation. So, lower inflammation was predictive of vitality, and cognitive function, and it was considered to be the only thing that was driving the aging process, or that could predict mortality aside from age itself. And I was thinking about how monocytes, macrophages, and neutrophils, these are the parts of the immune system that are the myeloid lineage, which is, you know, we have more of them when we're older.
They actually produce a lot of really nasty chemicals, hypochlorite, hydrogen peroxide. So, the myeloid lineage is producing lots of nasty inflammatory chemicals, so it'll be kind of interesting to look and see. I mean, I'm totally just speculating here, but if there's some way...if you to make a...if you could regenerate the immune system to resemble more of a youthful phenotype, first of all, it'll be interesting look at centenarians to see if they have more balance, right, if they have more of an immune system that has more lymphoid and myeloid, so it's not so asymmetric. That would be interesting to see, but also, whether or not, if that plays a role in healthy aging.
Valter: Yeah. I think we need to be careful with the inflammation as a cause of aging. I see it the other way around, I see it as the aging is the cause of inflammation. And that makes sense, right, because inflammation is really can come from dysregulation of immune cells and other cells in the body. So, yeah, so I think it's really the evidence, the inflammation is the driving...the driver is not there. There's very few studies actually showing that, you know, by increasing a little bit of inflammation, increase in aging, they're not there. It's possible but this doesn't seem likely, you know.
I look at it as much more in the sense of program, meaning that all organisms have a program, and this program is there to keep them healthy, and young up to a certain point, and now, there are ways to make these programs longer, or shorter, and I think the centenarian just happened to have programs that are stronger and longer. And then, when these programs fail, the inflammation is one of the things that you see as well, and it happens together with a lot of other problems. But certainly, inflammation, I mean, as a marker, is a very important one. So, if you look at C-reactive protein, for example, or Interleukin-6, in any intervention, they should do, you wanna see them coming down, and this is a good indication.
As we've done for our fasting-mimicking diet, where we've showed that almost every patient that...I mean, we showed a decrease in inflammation in the mice that were given the fasting-mimicking diet started at middle-aged. But we also saw it in the human population aged 20 to 70, where everybody they had high C-reactive protein came back down after 3 cycles the FMD, came back down to their normal levels. But again, that's probably indicating that the systems were not working properly, and now you bringing them back to a prior...you know, maybe you're regenerating part of the, you know, bone marrow and maybe also you killed some bad cells in the spleen, etc., etc. And so, the result of that is the last inflammatory markers that are being released. The liver, also, we've shown they undergo cycles of atrophy and regeneration. So, all of these organs are contributing to information, and so, it's important that with an intervention, you see also an effect in an inflammation, because it tells you that the intervention is working, the system is being reset back to a more youthful state.
The shrinking or wasting away of cells, organs, or tissues that may occur as part of a disease process, trauma, or aging.
A measurable substance in an organism that is indicative of some phenomenon such as disease, infection, or environmental exposure.
A person who is 100 or more years old.
A ring-shaped protein found in blood plasma. CRP levels rise in response to inflammation and infection or following a heart attack, surgery, or trauma. CRP is one of several proteins often referred to as acute phase reactants. Binding to phosphocholine expressed on the surface of dead or dying cells and some bacteria, CRP activates the complement system and promotes phagocytosis by macrophages, resulting in the clearance of apoptotic cells and bacteria. The high-sensitivity CRP test (hsCRP) measures very precise levels in the blood to identify low levels of inflammation associated with the risk of developing cardiovascular disease.
A diet that mimics the effects of fasting on markers associated with the stress resistance induced by prolonged fasting, including low levels of glucose and IGF-1, and high levels of ketone bodies and IGFBP-1. More importantly, evidence suggests these changes in the cellular milieu are associated with a sensitization of cancer cells to chemotherapeutic drugs while simultaneously also conferring greater stress resistance to healthy cells.[1] Evidence also continues to emerge that properties of the fasting-mimicking diet, particularly its ability to cause immune cell turnover, may also make it useful in the amelioration of auto-immune diseases like multiple sclerosis.[2]
Fasting-Mimicking Diet Breakdown
- Day 1 - consists of 1,090 total calories (10% protein, 55% fat and 34% carbohydrate)
- Days 2 through 5 - consists of 725 total calories (9% protein, 44% fat and 47% carbohydrate)
[1] Cheng, Chia-Wei, et al. "Prolonged fasting reduces IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration and reverse immunosuppression." Cell Stem Cell 14.6 (2014): 810-823. [2] Choi, In Young, et al. "A diet mimicking fasting promotes regeneration and reduces autoimmunity and multiple sclerosis symptoms." Cell Reports 15.10 (2016): 2136-2146.
A type of reactive oxygen species (ROS) that is generated through the activation of white bloods cells, usually in response to a viral or bacterial invader, but also as a consequence of general inflammation. Hypochlorite and other ROS can damage lipids, proteins, and DNA.
The gradual deterioration of the immune system brought on by natural age advancement. Immunosenescence is considered the most important reason for the increased rate of infections (and cancers) in older adults and is believed to be the diminished or exhausted function of the immune system that naturally occurs with aging.
A critical element of the body’s immune response. Inflammation occurs when the body is exposed to harmful stimuli, such as pathogens, damaged cells, or irritants. It is a protective response that involves immune cells, cell-signaling proteins, and pro-inflammatory factors. Acute inflammation occurs after minor injuries or infections and is characterized by local redness, swelling, or fever. Chronic inflammation occurs on the cellular level in response to toxins or other stressors and is often “invisible.” It plays a key role in the development of many chronic diseases, including cancer, cardiovascular disease, and diabetes.
A peptide hormone secreted by the beta cells of the pancreatic islets cells. Insulin maintains normal blood glucose levels by facilitating the uptake of glucose into cells; regulating carbohydrate, lipid, and protein metabolism; and promoting cell division and growth. Insulin resistance, a characteristic of type 2 diabetes, is a condition in which normal insulin levels do not produce a biological response, which can lead to high blood glucose levels.
A pro-inflammatory cytokine that plays an important role as a mediator of fever and the acute-phase response. IL-6 is rapidly induced in the context of infection, autoimmunity, or cancer and is produced by almost all stromal and immune cells. Many central homeostatic processes and immunological processes are influenced by IL-6, including the acute-phase response, glucose metabolism, hematopoiesis, regulation of the neuroendocrine system, hyperthermia, fatigue, and loss of appetite. IL-6 also plays a role as an anti-inflammatory cytokine through inhibition of TNF-alpha and IL-1 and activation of IL-1ra and IL-10.
A type of white blood cell. Macrophages engulf and digest cellular debris, foreign substances, microbes, cancer cells, and oxidized LDL in a process called phagocytosis. After phagocytizing oxidized LDL, macrophages are referred to as foam cells.
A type of white blood cell, also known as a granulocyte. Neutrophils are the most abundant form of blood cell, comprising approximately 60 percent of total cells. They ingest, kill, and digest microbial pathogens, and are the first cells recruited to acute sites of injury. Neutrophils can infiltrate brain structures, driving inflammation and increasing the risk for neurodegenerative disorders, such as Parkinson's disease and Alzheimer's disease.
The observable physical characteristics of an organism. Phenotype traits include height, weight, metabolic profile, and disease state. An individual’s phenotype is determined by both genetic and environmental factors.
Senescence is a response to stress in which damaged cells suspend normal growth and metabolism. While senescence is vital for embryonic development, wound healing, and cancer immunity, accumulation of senescent cells causes increases inflammation and participates in the phenotype of aging.
A person who is 110 years old or more.
Distinctive structures comprised of short, repetitive sequences of DNA located on the ends of chromosomes. Telomeres form a protective “cap” – a sort of disposable buffer that gradually shortens with age – that prevents chromosomes from losing genes or sticking to other chromosomes during cell division. When the telomeres on a cell’s chromosomes get too short, the chromosome reaches a “critical length,” and the cell stops dividing (senescence) or dies (apoptosis). Telomeres are replenished by the enzyme telomerase, a reverse transcriptase.
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