With rising life expectancy, older age is becoming an ever longer part of the human lifespan. During aging, the complex machinery of cells changes how it operates, with sometimes drastic consequences on the body. A new study, conducted by researchers at the Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), the Medical University of Vienna and the Johannes Kepler University Linz, now throws light on the role of lipid pathways in aging and the synchronization of cells. The study was published on January 18 in the journal Nature Aging.
Domagoj Cikes, previously a postdoc at IMBA in the group of Josef Penninger and now group leader at the Institute for Physiology and Pathophysiology at the Johannes Kepler University Linz, has long been interested in the complexities of aging, particularly in how aging affects metabolic processes in cells. “During aging, many well-oiled processes start to go haywire, including transcription, protein quality control, or cellular metabolic pathways. As we age, metabolic processes do not operate as well as in the young organisms and cells, leading to some of the physiological effects we see in older age, such as frailty.”
In the new study, Cikes and Josef Penninger – now also Professor for Personalized Medicine at the Medical University of Vienna, as well as Director of the Life Sciences Institute at the University of British Columbia and scientific manager of the Helmholtz Centre for Infection Research – investigated genes related to lipid metabolism that are dysregulated during aging. The researchers particularly looked at genes dysregulated in the skeletal muscle. “Collectively, skeletal muscle is our biggest organ, and fulfills important functions throughout our lifespan: Muscle is important for functionality and independence, and at the same time, muscle serves as metabolic sink for blood sugar and so controls important aspects of our health during our lifespan”, Cikes explains.
The researchers honed into the lipid glycerophosphocholine (GPC) and the enzyme that hydrolyses GPC, called Glycerophosphocholine Phosphodiesterase 1 (GPCPD1). The physiological function of this pathway was so far unknown, but Cikes and colleagues found that the pathway’s dynamics near perfectly mirrored the trajectory of aging: in younger age, the pathway is more functional, and higher amounts of enzyme and smaller amounts of the substrate it degrades, Glycerophosphocholine (GPC) is present in muscle tissue. In older age, fewer enzymes are present to degrade GPC, and so the level of GPC substrate increases.
“Following this observation, we asked how these changes connect with aging: Is this a cause or consequence of aging-related decline? And how does it affect the muscle and the health of our body?” adds Cikes. When the researchers mutated the enzyme in a mouse model, a stunning effect on glucose homeostasis could be seen: GPC accumulated in the muscle, and the mice became severely glucose intolerant, as glucose entry into the muscle tissue was severely inhibited. “This observation is extremely interesting, as one major hallmark of aging is that aged muscles cannot take up glucose any more as well as the young muscle, which in turn sets off a cascade of other health-related problems.” Several chronic diseases of aging are linked to high glucose levels, including inflammation, blood vessel stiffening, diabetes, and retina dysfunction. “So many health effects of aging occur downstream of this initial disruption of glucose homeostasis”, Cikes explains.
Indeed, the changes in the GPC pathway were also observed in older human individuals. “Comparing samples from younger and old individuals, we see that the enzyme decreases in middle-aged and old individuals and the substrate GPC rapidly increases with advanced age.” This observation also held true in patients with type 2 diabetes: Compared to healthy volunteers, the levels of the substrate GPC sharply increased, independent of how old the patients were. “Interestingly, dysfunction of the GPCPD1-GPC metabolic pathway is connected with aging and glucose homeostasis also in humans”, Cikes sums up. Given how Levels of GPC also correlate well with biological age, potentially making it a good biomarker for biological age that can be tracked with MRI.
In next steps, Cikes plans to investigate how the GPC pathway can be influenced – and how this affects the sequelae of aging. “Our next goals are to address, also in humans, how rejuvenation interventions affect the GPC pathway. Is the metabolite reduced when we exercise? How do intermittent fasting or caloric restriction affect the pathway? This could be an entry-way to intervene in the health-related effects of aging. Long term, we would like to develop a strategy to target the pathway itself to restore the capacity of the muscle in advanced age to metabolize the excess sugar in our bloodstream, preventing the onset of many age-related chronic conditions.”