In the fields of functional medicine, functional longevity and epigenetics, research is moving quickly – and so spending time delving into the scientific literature and discussing new findings with other experts in the field is essential. Last month, a new paper landed on my desk, published in the leading journal Cell. It lays out a comprehensive overview of the hallmarks of aging. Actually, it’s an update to the paper from the same authors published in 2013 which listed 9 hallmarks of aging (inflammation, dysbiosis, and autophagy now have their own categories in this latest version). If you’re so inclined you can read the paper for yourself here: Hallmarks of aging: An expanding universe. If you’d rather the summarized/adapted version, written in plain language and with a functional medicine/functional longevity lens, this blog is for you.
Incidentally, the Younger You program that I developed and that we use in our practice alongside broader functional medicine approaches is heavily rooted in the first of these hallmarks – epigenetic alterations – since I posit that it is the most likely central driver of aging changes. However, the Younger You interventions address ALL of the hallmarks of aging, since they are closely interrelated (as those of you who regularly follow my content will know). They are all essential considerations if we want to truly wrap our arms around the potential for extending healthspan and lifespan, as well as to tackle the huge societal and economic burdens of aging as it is today. In addition, even as the dietary and lifestyle intervention of the clinical pilot trial I led demonstrated the broad applicability of a standard longevity protocol (reducing biological age by over 3 years on average as compared to controls), we see even greater effectiveness when these principles are customized to the individual, as we’re able to do in clinic.
As always, let me know your thoughts on this content, where you are in your longevity journey, and feel free to chime in with thoughts on future content that would be helpful to you.
With thanks to Romilly Hodges for her contributions to this article.
The 12 hallmarks of aging and their relationship to functional medicine and functional longevity:
1. Epigenetic alterations
It’s no secret that I’m bullish on epigenetics being the likely driver (not just hallmark) of aging – i.e., I suspect aging is actually pre-programmed into our biology and that that programming resides in the layer of epigenetic marks on top of our genes. Not least because we have seen such remarkably high correlation coefficients in the ability of epigenetic-based (DNA methylation-based) biological age clocks to predict chronological age (although, extraordinarily, bio age clocks are superior predictors of morbidity and mortality than chronological age). Epigenetics also controls gene expression, including of those genes related to inflammation, protein folding, nutrient sensing and mitochondriopathy, which are also altered in aging, as you’ll read below.
Relationship to functional medicine/longevity: We have seen research (including from the study I led using the diet and lifestyle intervention now named Younger You) that indicates the potential for interventions to dial back epigenetic aging clocks. In looking at epigenetics, we cast a wide net over factors that can influence it including nutrients, dietary patterns, exercise, sleep, stress, toxins, medications, microbiome, and more. For each of these, functional medicine assessments and individualized interventions can be harnessed to promote optimal epigenetic activity.
Related content: See our blog post on What is Biological Aging and what does it have to do with methylation? Dr. Mitteldorf and I also discuss the pre-programming of the aging phenomenon in this podcast. (I am also keeping an eye on the Yamanaka Factors research coming out of a number of labs, including David Sinclair’s at Harvard, and Jeff Bezos’ Altos Lab, which is showing promise in directly manipulating the epigenome/methylome in animal models but has as yet challenges in translating to clinical use).
2. Chronic inflammation
“Inflammaging” is a term coined to describe the gradual increase of inflammation as we age. It has wide-ranging implications in disease-related activity such as arteriosclerosis, neuroinflammation, osteoarthritis and bone degradation. Inflammation is also clearly linked to all other hallmarks of aging both in its tendency to promote and result from other hallmarks, perpetuating an ongoing cycle of progressive aging pathology. Key inflammatory mediators of concern in the scientific literature include IL-6, TNF-alpha, IL1-beta, NFkappaB, and the NLRP3 inflammasome.
Relationship to functional medicine/longevity: Targeting the triggers and molecular mediators of inflammation is one of the most significant areas of work for functional medicine practitioners. As we age, we need to work harder to keep that inflammation under control – considering everything from intestinal barrier dysfunction, to toxin exposure, to dietary signals, to stress response patterns, to sleep habits, circadian rhythms and more. We also need to lean into using anti-inflammatory agents such as omega-3 fatty acids, and their derivative pro-resolving mediators, dietary patterns including ketogenic/ketogenic-leaning diets, vitamin D, epigenetic regulators (aka epinutrients such as curcumin from turmeric and the catechins found in green tea) for their impact on regulating gene expression related to inflammatory pathways, and more.
Related content:IFM article on Immune Aging and Therapeutic Targets and I highly recommend the IFM Immune Advanced Practice Module for which I am one of their long-time educators.
Microbes living in and on us are now widely understood to be intricately connected to health and disease. In part due to the gradual decline of our immune system’s effectiveness, and since one of our immune system’s roles is in shaping the diversity and species members of our microbiome, our aging microbiomes gradually lose diversity and become altered in their composition. Centenarians, on the other hand, are often reported as having microbiota that are similar to younger individuals. Scientists have been able to manipulate healthspan and lifespan in animal models simply via fecal microbiota transplantation, with concurrent reversal of aging hallmarks, cognitive function, fertility, and immune effectiveness. Human studies are starting to emerge too.
Relationship to functional medicine/longevity: Having a healthy gut and microbiome is another core focus area of functional medicine work. And there is no doubt that supporting a healthy microbiome has important protective effects on aging, age-related diseases, and longevity. In addition to fecal microbiota transplants (which are increasingly studied in clinical trials with beneficial effects, though not as yet for aging directly), probiotics such as Lactobacillus plantarum GKM3, postbiotics such as short chain fatty acids, as well as microbiome-shaping dietary interventions (including intermittent caloric restriction) have also shown beneficial effects on aging in animal studies. And we have a plethora of research confirming the connections between microbiome and age-related diseases, as well as a broader understanding of the effects of dietary patterns, sleep, stress, toxin exposure and other lifestyle factors on microbiome health. Not least, a healthy microbiome makes and activates many of the compounds we refer to as epinutrients so they can work their beneficial effects.
Related content: Dr. Fabian and I discuss the role of the gut microbiome in healthy aging in this podcast.
4. Deregulated nutrient sensing
Nutrient sensing networks are central regulators of cellular activity, including autophagy, protein synthesis, metabolism (including of glucose and fats), and the formation of mitochondria. They are nutrient “sensing” because their activity is highly responsive to nutrition and stress status. When nutrient sensing breaks down (as happens when we age or with excess caloric and simple carbohydrate intake), it can lead to excessive weight gain, glucose dysregulation, inflammation and inhibition of autophagy. Key nutrient signaling molecules of interest in this field include IGF-1, ALK, and MTOR (mammalian target of rapamycin). Hence the interest in rapamycin, which has been shown to disrupt MTOR activity and extend lifespan and reduce neurodegeneration and other age-related disease in animal models, even as it exacerbates some age-related concerns such as cataracts.
Relationship to functional medicine/longevity: Although rapamycin is not outside the arms of functional medicine and functional longevity, functional medicine practitioners start with optimizing diet and lifestyle. Introducing rapamycin as a longevity agent to someone who doesn’t have foundational pieces in place will not- I strongly suspect- yield valuable benefit and may, given the immunosuppressive potential of rapamycin, have untoward side effects. As we await human data on rapamycin for the longevity application, including optimal dosing strategies, a thorough diet and lifestyle foundation is essential for all longevity seekers, including the most strident biohackers.
We can favorably and potently influence MTOR activity through dietary manipulation. Caloric restriction has been shown to slow biological aging, likely in part due to its influence on MTOR and IGF-1. Additionally, ketogenic diets, low protein diets, and other forms of fasting are relevant here. Although, as I discussed in a recent blog on the benefits of consuming a high protein diet, research suggests the benefits of higher protein intake in the context of an overall healthy eating pattern (such as Younger You) probably override any potential negative influence on MTOR. A primary rationale for higher protein intake is the clear evidence around robust muscle mass (requiring sufficient protein intake) being associated with improved morbidity and mortality.
Related content: Dr. Redmond and I discuss metabolomics analysis in this podcast.
5. Mitochondrial dysfunction
With aging, mitochondrial dysfunction occurs including damaged mitochondrial DNA, loss of proteostasis that affects energy production (mitochondria are the energy generators for cells), and loss of mitochondrial membrane integrity (which causes a release of mitochondrial contents into the surrounding cellular cytoplasm) causes inflammation and can trigger cell death. In addition to interventions that protect mitochondrial function, researchers are also interested in supporting the healthy recycling of mitochondria, termed “mitophagy,” which I will cover under hallmark 9. Additionally, mitochondrial microproteins seem to correlate closely with the aging phenomenon.
Relationship to functional medicine/longevity: L-carnitine supplementation has demonstrated positive effects in both pre-frail individuals and elderly men, thought to be made possible by counteracting age-related declines in L-carnitine levels that limit the use of fatty acids for energy within the mitochondria. The mitochondrial microprotein MOTS-c declines with age but can be induced by exercise. In addition, functional medicine practitioners are trained to use a variety of nutrients for mitochondrial performance, as well as dietary and lifestyle inputs that modulate mitochondrial health and help resist decline.
6. Genomic instability
The integrity of our DNA (including both the DNA inside the cell nucleus as well as in our cells’ mitochondria) is challenged by exposure to external and internal chemical agents, pro-oxidants, errors in replication (as cells divide), and even spontaneous reactions. Our cells have an array of tools to try to repair that damage, but these lose efficiency with age. The result is an accumulation of genomic damage over time and, since our DNA is the foundational reference point for cellular activity, it is accompanied by increasingly dysfunctional cellular and organ activities. In other words, our cells and organs start to malfunction.
Relationship to functional medicine/longevity: Studies in humans and animals have found that enhanced DNA repair mechanisms are associated with increased longevity. Genes that code for DNA-regulating sirtuins, for instance, are of interest here because increased expression of, for instance, SIRT6 genes reduces genomic instability and extends lifespan. Sirtuins also respond to environmental cues (including nicotinamide mononucleotide or NMN) which makes them especially interesting for delaying aging. Not least, we pay close attention to minimizing internal and external sources of toxin and pro-oxidant exposure. Functional medicine also has tools to assess DNA damage, such as measuring 8-OHdG levels.
Related content: Harvard professor Dr. Sinclair and I discuss Sirtuins and NMN in this podcast.
7. Telomere attrition
Damage to, and the subsequent shortening of, telomeres (the end sections of your DNA strands) contribute to aging and age-related disease. Once upon a time, not too long ago, telomeres were considered THE biological hallmark of aging, but since have trended out of the limelight as other hallmarks have garnered more interest and the limitations of looking only at telomeres have been gradually teased out. However, telomeres are still important indicators of the aging process.
Relationship to functional medicine/longevity: The continued relevance of understanding telomere length is one reason it’s included in the biological age assessments we use. Although it’s harder to shift using diet and lifestyle interventions, there are some that have shown promise in delaying or even reversing telomere attrition such as restoring vitamin D sufficiency and one proprietary astragalus derivative. Understanding when someone has shorter telomere length also signals us as clinicians to dial up our work in other areas that can offset their increased risk for disease.
Related content: Dr. Raffaele and I review telomeres in aging in this podcast.
8. Loss of proteostasis
Loss of protein homeostasis (“proteostasis”) results in increasing amounts of dysfunctional proteins in the body – proteins that are either misfolded, misconfigured, or damaged in some way. Since proteins are what our body uses for all enzymatic reactions, repair, and waste removal, most of its communication, tissue maintenance and repair, and more, the gradual loss of protein function has wide-ranging effects. These include unrestrained inflammation, organ dysfunction, and even cancer development.
Relationship to functional medicine/longevity: Functional medicine approaches remove as many of the causes of protein dysfunction to minimize the loss of proteostasis. Certain system-based interventions have also been studied for their ability to support protein integrity and function including fasting, certain probiotics (e.g., Bacillus subtilis), and specific polyphenols (e.g, quercetin). Most of these studies are still in pre-clinical models, though clinical trials such as Dr. Bredesen’s using the ReCODE method have demonstrated the potential for cognitive improvements in humans (in this case, in early Alzheimer’s disease) using a systems-based approach including diet and lifestyle.
Related content: Dr. Bredesen and I discuss the root causes of neurodegenerative disease in this podcast.
9. Disabled macroautophagy
Autophagy is an essential process of removing cellular waste products. It is a component of proteostasis, although now proposed as a hallmark in its own right since loss of effective autophagy is a key contributor to the decline of organelle turnover and an accelerator of aging. (think of a healthy level of organelle turnover as organelle rejuvenation, if you will – and as being key to youthfulness). Macroautophagy is the most prevalent form of autophagy where unwanted cellular contents, including damaged organelles, are degraded within lysosomes or vacuoles.
Relationship to functional medicine/longevity: Stimulating autophagy via oral supplementation of spermidine (in mice) has been shown to extend longevity by up to 25%, along with measurably reduced cardiac aging. Other spermidine studies are similarly promising. In addition, nicotinamide mononucleotide and urolithin A, have been shown to induce beneficial mitophagy (microchondrial autophagy) in human clinical studies.
Related content: Dr. Singh and I discuss mitophagy (autophagy that is selective for mitochondria) in this podcast.
10. Cellular senescence
Senescent cells are those that have declined in function to the point that they stop dividing and in some cases, produce potent inflammatory compounds that aggressively damage the surrounding tissue. More and more cells become senescent in our organs and tissues as we age. It’s a process that is triggered in part by telomere shortening (importance of telomeres again), as well as DNA damage, mitochondrial damage, cancer development, viral or bacterial infections, oxidative damage, nutrient imbalance and mechanical stress. Cell senescence is implicated in several diseases including obesity-associated metabolic syndrome, diabetes (types I and II), heart disease, Alzheimer’s and Parkinson’s diseases. These connections have spurred research into senolytic agents that can eliminate senescent cells – some pharmaceutical (such as rapamycin again) but not all.
Relationship to functional medicine/longevity: Quercetin and fisetin are natural flavonoids with multiple targets and have been researched for their senolytic effects in animal models. These are compounds that are available in foods as well as supplementally. Forms of fasting, exercise, and maintaining healthy mitochondria also reduce senescence.
Related content: Dr. Cleaver and I discuss natural senolytics in this podcast.
11. Stem cell exhaustion
Pluripotent stem cells are the raw materials for cells in our body – they are “undifferentiated” cells that can become cells with a specific function (“differentiated”) such as blood cells, brain cells, heart muscle cells, bone cells, etc. Many differentiated cells are naturally able to “de-differentiate,” a process that the body uses for tissue repair. This involves the rejuvenation of cellular markers of aging including epigenetic clocks and epigenetic patterns. Even transient or partial “de-differentiation” resets the epigenome and transcriptome to a more youthful state. Since as stem cells and other cells age, they lose their renewal and differentiation ability, scientists are interested in interventions using stems cells or that trigger youthful reprogramming of other cells.
Relationship to functional medicine/longevity: There are hundreds of clinical trials using stem cells conducted around the world each year, and we have several systematic reviews (1,431 on PubMed at last count) evaluating the use of stem cells for specific conditions ranging from Crohn’s disease, to Autism Spectrum Disorder, to stroke, and even lung fibrosis in Covid-19 patients. Natural compounds such as curcumin are identified as having antioxidant mechanisms that support stem cell survival and activity, though these are just some of the many functional medicine interventions that address antioxidant levels and stem cell health.
Related content: Dr. Meraglia and I discuss stem cell therapies in this podcast.
12. Altered intercellular communication
Intercellular signaling is key to maintaining homeostasis and hormesis and is increasingly compromised with age. Among the effects of this is an increasing “chronification” of low-grade inflammation (“inflammaging”) and reduced immune responsiveness that gradually promote dysbiosis of the microbiome – your immune system is a key microbiome regulator. It also creates deficiencies in neural, neuroendocrine and hormonal signaling pathways that affect the adrenal system, blood pressure regulation, insulin sensitivity, and reproductive function.
Relationship to functional medicine/longevity: One of the biggest inhibitors of communication is cellular “noise” – everything from pro-oxidants (such as AGEs), stiffness in the extracellular matrix (triggering the release of matrix metalloproteases) which trigger damage-associated molecular patterns (DAMPs) which in turn activate pro-senescent, pro-fibrotic, and pro-inflammatory pathways. Functional medicine has numerous tools at its disposal to support improved signaling pathways such as glucosamine/chondroitin sulfate (which is supportive of a healthy extracellular matrix and when taken orally is associated with prolonged longevity in humans), and dietary patterns/supplements and lifestyle strategies that reduce homocysteine, AGEs, inflammation, and oxidative stress.
Resources on the Younger You program:
- Fitzgerald et al., (2021) Potential reversal of epigenetic age using a diet and lifestyle intervention: a pilot randomized clinical trial, Aging 13(7):9419-9432
- www.youngeryouprogram.com – for BioAge assessments, support programs, and more
- Individualized support in implementing the Younger You program through our clinic
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Hi! Great article! At the end of the article you state that ” Functional medicine has numerous tools at its disposal to support improved signaling pathways such as glucosamine/chondroitin sulfate (which is supportive of a healthy extracellular matrix . . .” The “healthy extracellular matrix” link took me to an article that seems to say the opposite: “Our data do not support the notion that oral intake of GlcN supplements promotes matrix build-up. The alleged positive effects of GlcN, if any, could potentially be because of effects not related to GlcN itself, but rather to other bioactive components in these products.” Can you please clarify this? Thank you! Dr. Fenske
Thank you, Dr. Fenske. We have Updated the citation link (although still with one indicating inhibition of ECM accumulation, but in a pathological situation where the inhibition may be beneficial). Glucosamine has multiple mechanisms of action and signaling effects, which we suspect lends modulating effects on ECM and direct signaling (including on inflammation). This article may also be of interest (below). – Team DrKF