Aging, clocks and metabolism
Circadian reprogramming identifies metabolic pathways of aging
About biological clocks
One of the most fascinating things about life is its incredible adaptability to environment and circumstance. Small but essential things, like nutrient availability or oxygen levels are sensed and responded to by our cells on a molecular level, initiating specialized survival programs to increase the odds of continued existence in an ever-changing environment.
Less known, but equally impressive, life even adapts to the “big” things, e.g. the planetary movement of earth which causes repetitive light-and-dark cycles on a 24h day. These diurnal rhythms (or circadian rhythms) are being felt and processed not only by mammals, but also by plants, fungi and even cyanobacteria. Which makes intuitive sense, since plant processes like leaf movement, growth, germination, oxygen exchange and photosynthetic ability need to be synchronized with the light cycles of its surrounding environment.
We humans are no exception, no matter if one is an early bird or a night owl, some good biological markers of our circadian rhythm processes are
- melatonin levels (absent in daytime, regulate sleep)
- body temperature (high in afternoon, low early morning)
- cortisol plasma-levels (high in the morning, low at midnight)
and they have been known and studied for decades. By investigating these “circadian” patterns, researchers discovered a “master clock”, a biological structure in the brain called the suprachiasmatic nucleus (SCN). This tiny part of the hypothalamus is directly situated above the optic chiasm, the place where the optic nerves from both eyes cross. One part of the SCN is directly in connection with photosensitive ganglion cells so light can induce gene expression changes, allowing these cells to synchronize with day-night rhythms. Another, less understood part of the SCN is considered light-independent, running a roughly 24h rhythm even in total darkness.
Additionally, the SCN “master clock” exerts control over rhythmic processes all throughout the body, socalled “peripheral clocks” or oscillators. Almost every tissue has rhythmic processes, including the adrenal gland, the lungs, pancreas and liver.
If you ever wondered how you body can handle trillions of cells working in concert to generate the beautiful you, synchronization is a big part of the answer.
Especially gene expression regulation, the process of when to produce which kind of proteins, can be understood in the abstract as a huge optimization problem for any organism. It’s a tough supply and demand system, optimized by evolution to reduce waste and increase efficiency. Timing is essential.
Let’s consider the timing of the ubiquitous experience of eating.
It has been observed for quite some time that many metabolites like glucose and lipids, or hormones like insulin or leptin, are oscillating in the blood in a circadian manner. Additionally, epidemiological studies showed that circadian misalignment (e.g. late-night eating) contributes to variety of metabolic diseases like hypertension, obesity and insulin resistance.
How come?
Once we consume food, our primary source of gaining biomaterial and energy, many metabolic processes are required to engage and “take proper care” of it. For simplicity, let us focus only on the liver, the “metabolic energy” hub of the body. The liver handles lipid homeostasis and cholesterol synthesis for the rest of the body. Both of these biochemical processes are regulated by SREBPs, a class of proteins known as transcription factors, master regulators of gene expression. These proteins make sure that all enzymes required in the biosynthesis of lipid macro-molecules are present for work. SREBPs themselves are regulated by insulin and sterol levels, but most importantly by eating. The SREBP’s lipogenic response to eating is in fact so strong that it can cause liver damage, when unregulated. Recently, researchers could show that at certain timepoints clock-genes keep the potent SREBPs in check, preventing over-activation (and diet-induced hepatic steatosis). These findings are suggestive of a molecular pathway by which circadian clock components anticipatorily regulate lipogenic responses to eating. To put it simply:
Clock genes know when we are (supposed to be) eating and fine-tune our metabolic response so our liver does not suffer damage.
Given this knowledge, we have some explanation for why certain bad eating habits (like late-night eating or binge eating) can be harmful and unhealthy for us; our body is just not prepared at these times.
However, do not despair of you are among those who enjoy the occasional midnight snack; researchers could also show that the negative effects can be remedied by late-night exercise or limiting the amount to small portions of 150kcals. Just avoid late-night fast-food or overly sugar-rich dishes and your liver will be fine too.
As a takeaway message, consider clock genes and metabolism as symbiotic partners working in concert for the health of your body.
Messing up clocks with age
Biological clocks do not measure time, rather they are considered rhythmic pacemakers to help us time biochemical processes with periodic events (24h long days) we all experience. A growing list of circadian-clock-controlled physiological processes includes metabolism, hormone secretion and cardiac function, all of which exhibit daily oscillations.
Somewhat ironically, time does not play nice with our biological clocks. The older we get, our daily cyclic fluctuations get less pronounced or even disrupted. Like an old car or a cluttered operating system, things do not run as smoothly as they used to any more. Not surprising.
What did surprise scientists was a body of contemporary data that showed how dysfunctional clock genes in the young can contribute to aging-associated pathologies usually only found in the elderly. Especially in the brain, disruption of the master clock is functionally connected with age-related decline in brain functions. Furthermore, genetic deletion of the clock gene BMAL1 in mice causes a premature aging phenotype and reduced life span. To sum up this widespread and anecdotal literature, scientists commonly assume that there is a link between between clocks and aging, mutually influencing each other. This opens up one intriguing possibility:
Biological clocks might be key players to combat a deadly disease we call “aging”.
Aging is a complicated disease that defies easy scientific explanations, similar to cancer.
Commonly, aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. […] hallmarks are: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication […]
One major problem for scientists is detangling the interconnectedness of these hallmarks, finding out common denominators, shared biochemical pathways or genes that can be targeted pharmacologically in the future. In general, anti-aging research is a quite unchartered territory when it comes to success stories.
One of the best documented and established anti-aging strategies is caloric restriction, reduced energy intake without malnutrition or starvation. From roundworm to fruitfly to primate, caloric restriction increases lifespan significantly.
Intriguingly, a rapidly growing body of data is now implicating caloric restriction with attenuated age-related decline in a clock genes dependent manner. Additionally, it has been documented that metabolic cues can function as zeitgebers (=”time givers”) for peripheral clocks, analogously to how light works as a zeitgeber for the SCN master clock.
Here we observe that the common denominator between biological clocks and increased life span is also metabolism.
Combine this with the notion that several hallmarks of aging are related to disruption of metabolic homeostasis, including nutrient sensing, mitochondrial dysfunction and abnormal signaling pathways; it becomes clear that most of what we consider “natural” aging processes might indeed just be increasing metabolic disorder. Which can be remedied.
Fixing clocks through metabolism as new anti-aging strategy?
This month, researchers from the University of California, Irving together with the Barcelona Institute of Science and Technology in Spain and the University of Iowa released their stunning work on aging and liver metabolism in the renowned scientific journal Cell.
In order to unravel the metabolic pathways underlying aging, caloric restriction and clock genes, the authors compared cohorts of young and old mice, fed freely or placed under caloric restriction via high-throughput transcriptome analysis.
The analysis revealed that the circadian transcriptome changes in the liver were enriched in transcripts involved in protein acetylation and NAD biosynthesis. Additionally, the authors could confirm that protein acetylation was indeed highly circadian and that in old mice, the rhythmicity was dampened. Furthermore, NAD has been considered a key metabolite of longevity, with age seeing progressive decline in intracellular concentration of this molecule.
Most strikingly, however, was that old mice under caloric restriction could return the acetylation patterns and NAD levels back to match the ones of their younger peers.
Our results centrally place the circadian NAD+ salvage pathway in mediating the beneficial effects of CR and reveal changes in rhythmic protein acetylation that implicate metabolic cues along the process of aging. -Sato et al, Cell, 2017
The authors study provides a comprehensive view on the underlying reason how caloric restriction has profound influence over rhythmic metabolite cycling in hepatic tissue. Yet most surprisingly, however, is the finding that core clock genes in aged mice remained stable.
We have shown that the circadian profiles of all core clock genes are unaltered during the aging process in the liver […], stressing that the clock mechanism is intact in the peripheral tissues of aged mice.-Sato et al, Cell, 2017
This is totally unexpected; we know that the clock has a huge influence on cell metabolism, we see that during aging rhythmic metabolic oscillations fail or dampen, and we know that metabolic cues serve as zeitgebers for the clock. Yet the clock remains unmoved.
These findings are backed by another collaborating group working with stem cells (SCs) and age-acquired DNA damage responses. Equally surprising, they showed that also in epidermal stem cells, while the transcriptome changes, clock genes’ cyclic pattern remains stable during aging. They come to the conclusion that the transcriptome reprogramming observed seems to be not directly dependent on the master clock genes like BMAL1, but rather represent an adaptation to old-age stressors like DNA damage.
[…]we have determined that aged SCs remain robustly rhythmic. Intriguingly, however, the rhythmic functions of aged SCs are rewired such that they adapt to the new conditions of stress associated with the aged environment.
Importantly, deletion of circadian clock components did not reproduce the hallmarks of this reprogramming, underscoring that rewiring, rather than arrhythmia, is associated with physiological aging.- Solanas et al., Cell, 2017
This leaves us with a somewhat open-ended conclusion:
The master clock still runs on time in aged tissues, it’s just that the cell’s processes seem to have adapted to a different schedule.
So a quick fix for the master clock might not be the magical solution to aging after all. It is more complicated than that. Like always, further studies are needed to look deeper and find out how rhythmic processes like acetylation, NAD levels or DNA damage responses adopt a different dynamic with increased age, and how to fix that. We do not even know yet why or when cells might decide to change those long-working process schedules in the first place, but be sure about one thing:
Day and night, there are some scientists working on it, until they are of old age themselves.
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