Why Skin Health is the Ultimate Test of Longevity
Team DrKF sat down with Dr. Fitzgerald to pose some questions about the “state of the state” of longevity research, current controversies and future directions, and where she sees her work fitting into it.
When it comes to defining and using measures of biological age, where does the science currently stand?
To understand where we currently stand, and why changes are afoot, we have to first consider where we’ve come from. When Steve Horvath at UCLA released the first epigenetic biological age clock in 2013 it marked the entry of longevity medicine into the mainstream (referred to as biogerontology in science, anti-aging medicine in some clinical circles). The epigenetic clocks appeared to be the most reliable tools yet to measure (or at least glimpse at) the aging phenomenon thereby opening a door into what might slow- or even reverse- them. Although data at the time suggested the clocks were not apparently responsive to treatments or lifestyle inputs, that changed in 2019 with the publication of two papers- the TRIIM and Vitamin D studies.
The TRIIM trial boldly claimed “biological age reversal” and this title was made all the more momentous because Horvath himself was a principal author. Our study was published in 2021 and was the first randomized controlled study using a diet and lifestyle intervention to show apparent biological age reversal (which we opted to conservatively qualify by adding “potential” to the title). Since those early years, the epigenetic clocks have been used in myriad investigations tracking the effects that both appear to slow them down or speed them up.
Fast forward to 2024 and we appear to be sitting at a crossroads of sorts with regards to measuring aging. Summits are being held by premier scientists to tussle with challenging questions. Where the clocks fit sits at the epicenter of these debates: Do the epigenetic clocks measure biological age in its entirety? Are they surrogate measures of aging? Or do they measure one component of a remarkably complex process that is still being defined in-and-of-itself?
The reality is that scientists are still teasing these answers out. And while it seems clear that epigenetic clocks measuring biological aging (or some aspect of it) are important next steps in the journey, the reckoning happening now might require us to take a deep breath and continue to acknowledge these unknowns openly and honestly by qualifying our terms as we use them.
You will see the language we use on the platform, the conversations we have in written and audio form- evolve as the science evolves. I still sit firmly in the camp that there is great utility in using the epigenetic clocks as a part of an investigation. And the information we can glean from studying gene expression through epigenetics more broadly is here to stay… And I still personally believe the science on cellular rejuvenation suggests that manipulating the epigenetic landscape may be the strongest entry point for what we are cautiously calling/not calling biological age reversal. But that’s not at the expense of other non-epigenetic measures, nor is it discounting the importance of other measures.
“Calling/not calling biological age reversal”… Could you say more about that?
We know that we are still in the early stages of understanding biological age measurement, that the clocks continue to evolve, and that we have to be cautious about interpreting and languaging research findings. Our intention has always been to make those caveats clear.
Believe me, I appreciate Peter Attia’s comments to me around someone 60 years old bragging on having a bio age of a 30 year old! Does this mean said person is living a 30-year-old’s life expectancy? Highly likely not with the current interventions being used today. But is this individual in tip top shape, and is that being reflected in the clock findings? Likely yes. I do think we should consider a different measure for these clocks, such as the rate of aging as the Pace of Aging uses. Either way, this is an important conversation that will evolve with time and understanding. People ask me all the time how young they can expect to get using the Younger You program. I can assure them they won’t return to their teen years. It’s a healthy dietary and lifestyle pattern. But can many anticipate getting healthier, and could that be reflected in a drop in their epigenetic age? Yes, I think this is possible.
Regarding the important issue of use of terminology, the current debate is centered specifically on terms such as “biological age reversal.” Clearly there’s a reckoning among biogerontologists happening as to how to best describe this potential phenomenon. This is creating a certain amount of fluidity. I have to reiterate, when we were writing our first paper, our guide was the TRIMM study, which used “Reversal of epigenetic aging…” We did couch this further by adding “Potential… reversal of epigenetic aging.”
How does your work compare to other gerontology and “biological age” (terminology challenges noted) research?
We are at a stage where many researchers are “stretching the legs” of these clocks which has primarily involved retrospectively analyzing existing large data sets to see if diet, lifestyle, and pharmaceutical changes match with the biological age changes we might expect to see. There are interesting findings that have been gleaned, but this is very different from our small, but deliberately-designed, prospective intervention research.
Reflecting on what we have been, and are, seeking to do – and this is so far unique in the field as far as we know – is to apply an intervention that attempts to deliberately target DNA methylation/epigenetics at a broad level using dietary and lifestyle factors that provide substrate, cofactors, or potential “regulators” of DNA methylation such as dietary polyphenols. These factors arise from mechanistic studies, animal studies, observational human data, and general nutrition biochemistry. We have been using this intervention in our clinical work for a decade and published a white paper on it in 2016. The connection to biological age actually evolved from that later on as the DNAm clocks became more prominent – it wasn’t the original starting point.
Our original 2021 pilot randomized and controlled clinical study was conducted through the Helfgott Research Institute. Guidance on study design and data analysis came from Dr. Moshe Szyf and his team at McGill – Dr. Szyf coauthored the paper with us and he is considered a pioneer and prolific publisher in the field of epigenetics. His work, along with that of Dr. Randy Jirtle and others looking at dietary/lifestyle inputs on the epigenome and gene expression (you may have heard me talk about their Agouti mouse studies? Here and here) massively influenced our starting point and ongoing thinking.
Our case series paper in women followed in 2023. The rationale for the case series was that we wanted to share the data (albeit limited) in women we had available, since women are typically underserved in scientific research.
Pilot trials and case series are sometimes seen as less valuable than those large data analyses. What is your view on that?
Our work is certainly very different from the large dataset analysis of most other publications. However, I would argue that pilot clinical trials and even case series are important for the process of discovery. Early in my career, I published a number of case studies in the literature and a collection of them in a book directed towards professionals in functional medicine. I understand that case studies are not broadly embraced by the academic/scientific community, but they are appreciated by clinicians. After all, large data analyses can give us average trends, but only a minute fraction of your patient base will actually sit on the “average” trend line – almost everyone is somewhere above or below that. This is where the science and the art of individualized medicine meet. Not least, case studies can inform the questions that are then used in clinical research studies.
I also feel strongly that we need to be using these (safe) interventions in humans. Much of the science in the longevity research space has been in animal models which, as we have seen, are challenging to translate to human outcomes. I think we can accelerate our learning by using human trials, and it’s much easier to do that with smart, tailored dietary and lifestyle interventions that are built on components that are time-tested for safety – foods, exercise, sleep, etc. Make no mistake, I am very excited about some of the more radical interventions being readied for human trials (Yamanaka factors, Sebastiano and others) but diet and lifestyle inputs are these unavoidable first steps. We cannot jump over the fact that we need to eat/not to eat, sleep, exercise, connect, etc and if we want to live well and long, these pieces need to be a part of any longevity plan.
What are you currently working on or planning to work on?
We are under IRB and want to continue to explore our initial program, likely evolve it based on what we’re learning, and publish on it as appropriate. Although we used one of the first generation clocks in our original papers, we’re also interested in the general methylome and are now using the Dunedin Pace of Aging clock.
We are also writing up our EWAS findings from the original 2021 cohort and are also close to submitting a paper analyzing the potential influence of the various dietary components – even as we recognize the clocks as possible surrogate markers of biological aging, we have always been keen to look beyond them. I am interested in continuing to explore the connections between dietary and lifestyle inputs, and epigenetics/gene expression in general – again, looking beyond the clocks alone.
We also appreciate that there are other important parameters associated with increased risk for morbidity and mortality, such as grip strength and VO2 max. The Pace of Aging (in addition to being affordable and easy to collect), was built on these and other well-established measurements.
We understand there are many unanswered questions and we look forward to continuing the conversation from our corner of the globe, where we will continue to explore the influence of a polyphenol-dense, complex dietary pattern on the epigenome, including DNA methylation patterns, and select biomarkers of health.
Ps. Dear readers – if there is any topic that you would like us to explore and share on further, either through our writing, in a podcast, or via a webinar, please let us know in the comments below.
Related posts
