At the molecular level, we may not age gracefully; that is, we may not follow a continuous, linear downward slope. Instead, we may fall precipitously after we lose control of our exquisitely balanced anti-aging programs, sometime in our 50s. These findings, derived from a study of tissue-coding and noncoding RNA, may help explain why human disease burden increases so sharply from the sixth decade of life onward. They may also lead to therapies that enhance longevity, provided the natural termination of protective gene expression patterns does not indicate that they have outlived their usefulness.
The study is the culmination of two decades of work initiated at the Karolinska Institute by Claes Wahlestedt, MD, PhD, now of the University of Miami Miller School of Medicine, and Jamie Timmons, PhD, now of King’s College London and Stirling University Science Park, United Kingdom. They developed a new method for quantifying comprehensive gene expression patterns, which they applied to carefully curated sets of tissue samples from humans at various ages.
Focusing primarily on muscle and brain, the scientists discovered molecular patterns in humans that align well with those previously observed in short-lived species. This included a dominant role for the so-called mTOR protein complex—a mechanism that regulates numerous protective cell programs—as well as mitochondrial reactive oxygen species production. These two cellular mechanisms combined to explain about two-thirds of the molecular aging profile in humans.
Detailed findings appeared June 6 in the journal Aging Cell, in an article titled, “Longevity‐related molecular pathways are subject to midlife ‘switch’ in humans.” The article describes the quantification of protein-coding and long noncoding RNA (lncRNA), as well as the identification of roughly 800 transcripts tracking with age up to about 60 years. In other words, the transcripts constitute a molecular signature that remains active until up to the sixth decade of human life but largely dissipates thereafter.
“In silico analysis demonstrated that this temporary linear ‘signature’ was regulated by drugs, which reduce mortality or extend life span in model organisms, including inhibitors that mimicked and activators that opposed the signature,” wrote the article’s authors. “We profiled Rapamycin in nondividing primary human myotubes and determined the transcript signature for reactive oxygen species in neurons, confirming that our age signature was largely regulated in the ‘pro‐longevity’ direction.
“Genes ECSIT, UNC13, and SKAP2 contributed to a network that did not respond to Rapamycin and was associated with ‘neuron apoptotic processes’” in protein–protein interaction analysis. ECSIT links inflammation with the continued age‐related downwards trajectory of mitochondrial complex I gene expression, implying that sustained inhibition of ECSIT may be maladaptive.”
The scientists emphasized that their observations link, for the first time, model organism longevity programs with the endogenous but temporary genome‐wide responses to aging in humans, revealing a pattern that may ultimately underpin personalized rates of health span.
“Our study revealed that the complexity of regulation of aging programs may be much greater in humans as compared to other species,” Wahlestedt said. “This is related to our more complex genome, which may have evolved to allow for longer and healthier lifespan. But perhaps humans were not really meant to last beyond their 50s.”
“Beyond the need to consider different ‘phases’ of molecular aging, clinical variables such as aerobic capacity and insulin resistance are also important to quantify,” Timmons added. “They interact with some of the same genes as aging, are partly inherited, and are important predictors of health. We were able to look at these for the first time when modeling human aging.”
While the key protein regulators of longevity and healthspan in short-lived animals have been found for the first time to be central to human molecular aging, this new study also determined that many little-studied so-called non-protein-coding genes are involved in human aging. Considered the “dark matter” of the human genome, these non-protein-coding genes are widely present in human cells, but often not found in lower organisms. It now appears they could play an important role in fine-tuning the molecular features of aging.
“We’ve demonstrated that the most valid of anti-aging programs are naturally active in humans and for some reason stop when we reach our 50s,” Wahlestedt asserted. “This not only provides a specific time window to now study human aging, it also indicates that these established anti-aging strategies may no longer be effective (if too active there can be side effects), and so new approaches will be needed in long-lived humans.”
If one wishes to boost these anti-aging programs with drugs, nutrients, or lifestyle choices, is it too late to start by the time you reach your 60s? Possibly, advised Wahlestedt—at least if you hope to benefit fully from such interventions.
