This week, Tony Wyss-Coray and I released a review paper in Nature Medicine titled “Biological Aging Clocks in Health and Disease.” While the paper covers complex concepts that may be challenging for those outside the life sciences, it introduces groundbreaking ideas with significant implications for medicine’s future. In this edition of Ground Truths, I aim to break things down into four main sections: (1) the misleading nature of chronological aging; (2) how aging synchronizes across the body, emphasizing organ clocks; (3) the role of cellular clocks and aging regulators; and (4) the relevance for everyday medical practices.
It’s widely understood that people age at different rates. Take the 90-year-old who seems decades younger and has never been sick—this is often labeled as a “Wellderly” or “Super Ager.” However, the general belief has been that aging follows a steady, predictable trajectory, as noted on the calendar. That’s what we mean by the “chronological illusion,” and new research has debunked that notion, revealing three significant waves of aging occurring at approximately ages 34, 60, and 78.
Interestingly, our organs also age at different rates, which scientists might not have discovered without advanced proteomics and AI analytics. By examining thousands of proteins from a blood sample, we can determine which proteins correlate with specific organs and the immune system. One valuable example comes from the UK’s National Survey of Health and Development, which follows individuals born in the same week in 1946. When they reached age 63, proteomic data revealed about a ten-year difference in organ and immune system aging among participants. Notably, individuals exhibited variances between their chronological age and organ age, with evidence correlating faster aging of organs with specific diseases, like heart failure or Alzheimer’s.
This asynchronous aging process has been noted in numerous studies and has shown connections to lifestyle factors, such as alcohol consumption and education. In our review, we highlighted how adverse life experiences, like parental divorce, can negatively impact organ clocks, while positives like childhood socioeconomic status and physical activity can help protect health.
Discovering these organ clocks is significant, but the exploration goes further into cell clocks. Remarkably, there’s now the ability to track aging in various cell types, like brain astrocytes, through proteins found in the blood. Research before our review found that roughly one in four participants showed signs of accelerated aging in at least one cell type. For instance, older astrocytes (brain cells) were linked to a 12.6 times higher likelihood of developing Alzheimer’s.
Furthermore, the risk of Alzheimer’s increased notably for individuals with the APOE4 gene variant, especially those with two copies of it, even when considering the age of their astrocytes. These findings provide critical insight into determining Alzheimer’s risk in ways that weren’t previously available.
Consistent patterns emerged from both organ and cell clock studies, revealing that increased evidence of accelerated aging correlates with higher mortality rates. A key takeaway is that normal aging in the brain and immune system suggests a higher chance of survival over extended periods. These two systems seem to act as critical regulators of the overall aging process, supporting resilience in the face of aging in other organs.
Although we’re not ready to fully implement organ and cell clocks clinically, progress is being made. I’ve even had my own organ clocks assessed through a beta-testing company. Numerous studies are ongoing to further validate these findings. We’re about to start a rigorous trial targeting individuals at high risk for Alzheimer’s, focusing on aggressive lifestyle changes and measuring biological markers at the beginning and end of the study.
Looking back on the evolution of aging research, the foundation for assessing biological aging began over 15 years ago with Steve Horvath’s work on DNA methylation clocks. This initial framework has since expanded, incorporating data from various biological sources, leading to more precise assessments at the organ and cellular levels. Our review summarizes six generations of biological clocks, which have crucial implications for medicine and the possibility of reversing aging.
Identifying accelerated aging in organs could pave new avenues for prevention. For instance, someone at risk for heart disease exhibiting early aging signs in their arteries might offer a new understanding of risk. The same applies to the immune system, where we currently lack assessment tools but can now quantify aging at both systemic and cellular levels.
Despite these advances, we still face challenges with existing aging clocks sold directly to consumers without the required standardization and reliability. I recommend against purchasing these tests for now, as the most promising approaches are still in research phases. That said, we expect improvements to come soon, contingent upon validation and standardization to lower costs.
As we continue to advance in this field using large datasets and AI, it’s essential to acknowledge just how far we’ve come. I hope this discussion has clarified the complexities involved and made it accessible for all. For those following Ground Truths, you might remember my enthusiasm over organ clocks’ discovery last year. The pace of progress has only accelerated since then, showing promise for a significant shift in how we perceive aging in medicine.
This transition from merely counting years to understanding biological aging in detail may take time, yet it signals profound changes ahead. It’s not about dismissing chronological age altogether; rather, it emphasizes the potential to understand and possibly modify biological age. This, I believe, represents a monumental leap in aging science and holds the key to healthier lives and disease prevention in the future.
