The Drivers of Age-Related Diseases

New insights on the pivotal role of Immunosenescence and Inflammaging

We’ve known that our immune system and the process of inflammation are tightly intertwined and are affected by aging. The terms immunosenescence and inflammaging have been coined to reflect that. In the past few weeks there have been a number of important publications that tell us much more about their pivotal role for influencing the major age-related diseases and our healthspan. In this edition of Ground Truths I will review 4 key papers and present a unified model that brings the findings together.

1. The proteins from senescent cells predict age-related clinical outcomes

In an elegant study by researchers at the NIH and Johns Hopkins, senescent monocytes were isolated from the blood for more than 1,000 participants in the Baltimore Longitudinal Study of Aging (BLSA). As shown below, the senescent monocytes cells are differentiated by secreting proteins, what is known as SASP for senescence-associated secretory phenotype. The proteins secreted by these monocytes were characterized by mass-spectrometry and compared with body-wide high-throughput proteomics using Somascan (which assayed ~7,000 proteins)from the plasma of the BLSA participants. Over 1500 proteins in common were analyzed using machine learning (LASSO) and shown to predict various clinical traits. These included walk speed, chair to stand pace (and other components of the frailty index), systolic and diastolic blood pressure, fasting glucose, hemoglobin A1c, lipids, inflammation markers of C-reactive protein (CRP) and interleukin-6 (IL-6), DEXA scan results, and waist size. All of this was further validated in another cohort.

While this study does not prove cause and effect relationships, it certainly provides new data on SASP as a biomarker of aging and also highlights the a close relationship with diverse clinical traits and outcomes. Some of the strategies to reverse aging are relying on eradication of senescent cells (known as senolytics) for which the findings in this study may be useful.

2. A new epigenetic age clock connects the dots between aging, the immune system, inflammation and lifestyle factors

Researchers at the Buck Institute for Research on Aging and collaborators published a new DNA methylation clock called DNAm IC, where IC stands for intrinsic capacity, the “sum of an individual’s physical and mental capacities.” The cohort used to construct the clock had over 1,000 individuals aged 20 to 102 years and was then validated in the Framingham Heart Study participants. Here is a schematic of the study:

It outperformed previously validated and widely used epigenetic clocks such as the Horvath and Hannum clocks, and was as good or better than PhenoAge (as shown below, and also GrimAge, not in the Figure) for predicting all-cause mortality.

A higher DNAm IC was linked to lower CD8+ exhausted T cells, higher CD8+ naive T cells, and increased CD28 expression, which relates to T cell activation and proliferation and decreases with age. A high DNAm IC was also correlated with a low iAge, an immune system metric for chronic age-related inflammation. Individuals with high DNAm IC were more physically active, had better cognitive scores, more handgrip strength, consumed more fish and had increased levels of omega-3 fatty acids. High DNAm IC were inversely associated with inflammation markers such as IL-6 and CRP.

3. People with a fast pace of aging had an increased risk of cognitive impairment, age-related diseases, disability, and mortality

Columbia University researchers published an important study of 2 cohorts, the US Health and Retirement Study (HRS) and the UK English Longitudinal Study of Aging (ELSA). In over a total of 19,000 participants with multiple assessments over more than 10-15 years, which included inflammation makers (CRP and Cystatin), hemoglobin A1c, handgrip strength, balance, walk speed, lung function, and blood pressure.

Shown below is survival related to Pace of Aging at left and the outcomes at right (CIND-cognitively impaired, not demented, ADL-activities of daily living, reflecting disability). The Pace of Aging composite relies on easy to obtain metrics, not using DNA methylation makers, and predicted the outcomes as well or better than the widely used epigenetic clocks known as DunedinPACE of PC Grim Age. Overall, men aged faster than women and the pace of aging picked up in people of advanced age.

4. The Importance of “Immune Resilience” for Healthspan

In Aging Cell, UT San Antonio researchers and collaborators published an analysis for more than 17,500 individuals from multiple cohorts that identified “immune resilience (IR)”—defined as the capacity to resist disease despite aging and inflammation. Their core mechanistic finding was that TCF7, a transcription factor that is vital for T cell function, counters inflammaging and immunosenescence, and is central to healthspan. In the Table below, you can see their finding lines up with all the other studies of gene expression, adjusted for age and sex, whereby the signatures of more inflammaging or immunosenescence align with shorter lifespan, while those with less inflammation or immune system degradation track with longer lifespan.

A Unified Model of I/I

These new studies add to the previous ones that I have reviewed in Ground Truths with organ clocks and high-throughput proteomics. I’ve also gone into much more depth for this topic in my book SUPER AGERS. The totality of evidence supports immunosenescence and inflammaging (I/I) at center stage, the drivers of the 3 major age-related diseases.

The new studies reviewed here, along with several others, lead to a unified model that considers many ways that we can reduce I/I , pulling together evidence from a body of data on lifestyle factors, environmental toxins, the GLP-1 drug effects, and vaccines.

An anti-inflammatory diet that is predominantly plant-based, Mediterranean, low in red meat, and low in ultraprocessed foods, has been closely linked with healthy aging (See my Ground Truths on Optimal Diet). Note that too high a protein intake, particularly from animal sources, promotes inflammation and has been shown to increase atherosclerosis in the experimental model. Also, the important of visceral adiposity, with fat cells producing inflammatory mediators (adipokines) and promoting inflammation fits in this category. The new epigenetic clock study reviewed above was again notable for connecting a healthy diet and DNAm IC.

As reviewed previously, exercise helps maintain the integrity of the immune system and a favorable impact on epigenetic clocks (here and here), all linked to healthy aging. We’ve recently seen how 3 large natural experiments of Shingles vaccines pointed to a 20-25% reduction of dementia, mostly Alzheimer’s, which would be considered to be a breakthrough if this was derived from a drug. Undoubtedly, this has something to do with revving up the immune system in older individuals.

Sleep regularity and quality are critical to promote brain health, reduce neuroinflammation, and this also extends to body-wide inflammation and favorable modulation of the immune system. I recently did a podcast with Matt Walker on this topic which will be posted soon.

Environmental toxins that include air pollution, microplastics and nanoplastics, and forever chemicals, all of which promote inflammation and the age-related diseases. They are presently unchecked and are contributing in the opposite direction of healthy lifestyle factors.

The GLP-1 family of drugs, including semaglutide and tirzepatide, have been shown to reduce body-wide and brain inflammation, both in experimental models and in people even before there is evidence of weight loss. This effect is currently being assessed in 2 large trials of preventing Alzheimer’s disease. Moreover, there are many other gut hormone mimetics (agonists) in the pipeline, which talk to the immune system and the brain, which will be tested independently and in combination, in the future for their potent I/I effects.

Concluding Remarks

While everything we know generally fits into this model, it is clearly reductionist, oversimplified. In thinking about how the human body works, it’s of course never this straightforward. However, we create models for their usefulness and I believe all of the data over recent years gets us to this synthesis for I/I. There is one problem to highlight. While we’re learning a lot from recent publications, we don’t currently have a way to assess the immune system in people and our markers for inflammation (CRP, IL-6, and cytostatin) are not adequate by themselves. If we’re going to make a push too extend healthspan at the individual level, we will need to have better, practical, inexpensive ways to get at I/I in older adults. I’ve called for the need to have an immunome and better, supplementary inflammation markers, especially now that the evidence for I/I as principal drivers has become so robust.

All of this supports my firm belief that we have an extraordinary opportunity to prevent the major age-related diseases now that was not previously possible. It combines advances made in understanding lifestyle plus factors, multimodal A.I., and new interventions to control I/I. It’s the central premise I advance in SUPER AGERS and why I think we’re at a partially momentous time to make a difference for extend healthspan in the future. That’s without the need for reversing aging, or the unmitigated torrent of pseudoscience from longevity clinics, longevity companies, unproven procedures and total body imaging, and anti-aging supplements, all of which are void of any meaningful data.

The other side note is the sad truth that with the current, profound US defunding of biomedical research we will lose valuable time to pursue this opportunity— to use our I/I enhanced knowledge to extend healthspan and prevent the major diseases. Ironically, primary prevention has enormous economic value and advantage compared to the cost of treatment of any of these age-related diseases. No less the rarity of finding actual cures.

We’re staring at the prevention potential right now, yet stymied from going after it full throttle.

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These are the first couple of independent reviews that I’ve seen:

WSJ by David Shaywitz gift link

Substack Alex Zhavoronkov link

And, lastly….

Join me for a live chat with Prof Devi Sridhar: https://open.substack.com/live-stream/34109?r=158dl&utm_medium=ios on Tuesday, June 17th 10 AM PST on her new book