For many there is no greater disappointment than startling awake before the clock radio goes off, or finding it impossible to sleep after flying cross-country and not yet making the adjustment to a new time zone. The synchronized dance of proteins and enzymes within our cells that help articulate our circadian rhythms can explain both of these relatively common experiences. Surprisingly, some scientists who delve into this area of research now believe similar rhythms and patterns might regulate aging.

“Animals and plants have biological clocks that help to regulate circadian cycles, seasonal rhythms, growth, development, and sexual maturity,” J.J. Mitteldorf wrote in a recent article. “It is reasonable to suspect that the timing of senescence is also influenced by one or more biological clocks.”

Look First to the Brain

The hypothalamus is a very small portion (about the size of a shelled walnut) of the brain that connects, via the pituitary gland, the nervous system with the endocrine system. This communication link between nerves and hormones regulates primitive instincts such as hunger and thirst, while also controlling body temperature. Within the hypothalamus is the suprachiasmatic nucleus (SCN), a collection of neurons that are collectively about the size of a grain of rice. This structure, commonly referred to as our body’s “clock,” controls the circadian rhythms that govern when we sleep and wake. This is accomplished through the synchronized actions of thousands of neurons contained within it. Inside each individual SCN neuron, the protein product of a particular gene turns off production of more protein resulting in molecular oscillation that influences hormones and changes in body temperature. This oscillation, then, synchronizes the many local “clocks” located in organs and tissues throughout the body.

In fact, scientists often describe the body as a collection of clocks. Although it paints an instructive picture, there are many details involved in how our extraordinarily complex bodies work. In each cell within our body, for example, a protein called PERIOD (PER) exists. The number of PER proteins in each cell rises and falls during a 24 hour cycle, repeating endlessly over time. Levels of PER protein are guided by two genes, CLOCK and BMAL1. The level of PER protein in each cell rises during daylight and reaches its peak around evening. Yet this peak activity somehow inhibits CLOCK and BMAL, thereby reducing its own level during nighttime hours, when falling PER protein levels cause biological systems to slow: blood pressure drops, heart rate slows, and mental processes wind down.

"We roughly knew what mechanism told the clock to wind down at night, but we didn't know what activated us again in the morning,” Satchindananda Panda, an associate professor in Salk's Regulatory Biology Laboratory, stated in a press release. In a recent study intended to discover the wake up mechanism, Panda and his team searched for, and identified JARID1a, a type of enzyme involved in normal cycling, one that helped “wake up” an organism on both the cellular and behavioral level. The team genetically modified human and mouse cells to under-produce JARID1a; they found the PER protein did not rise to its normal peak each day.

Next, they genetically altered fruit flies in a similar manner and discovered that the flies soon lost all track of time. They had no idea when to sleep or wake, and took frequent naps throughout the day and night. The team also discovered through their experiments that JARID1a reactivates CLOCK and BMAL1 by countering the action of a brake protein HDAC1. In other words, JARID1a helps to wake us up in the morning.

“Now that we've found it, we can explore more deeply how our biological clocks malfunction as we get older and develop chronic illness," Panda suggested. Other researchers would like to take such ideas even further and investigate whether the aging process itself might be an illness they can prevent.

Resetting the Clock

In fact, J.J. Mitteldorf, of the Department of Ecology and Evolutionary Biology at the University of Arizona, argues that just as our biological clocks regulate circadian rhythms and growth, aging is similarly programmed by a clock hidden within our metabolism. Noting that aging is a metabolic function and genes have been discovered that increase life span when inactivated, Mitteldorf also argues that some animals and many plants are known to grow indefinitely larger and more fertile throughout their lives. In particular, he focuses on gene regulation.

“Gene expression itself forms a kind of aging clock,” Mitteldorf wrote. “Time is maintained within the signal networks of metabolism, and a running record of the organism’s age is imprinted in the methylation state of the genome.” As he explains, the gene expression products are part of a signal cascade that affect all aspects of our body’s metabolism, yet they are also involved in methyl transferases — cellular processes that silence and regulate genes. Because of this, Mitteldorf suggests such processes may also increment the aging clock. “The methylation state of the genome, within stem cells in particular, may be a promising place to look for a stored record of organismic age that informs the body’s growth, development and senescence,” Mitteldorf wrote. Once the clock is found, he suggests, time might be reset.

Sources: Panda S, DiTacchio L, Le HD, et al. Histone Lysine Demethylase JARID1a Activates CLOCK-BMAL1 and Influences the Circadian Clock. Science. 2011.

Mitteldorf JJ. How does the body know how old it is? Introducing the epigenetic clock hypothesis. Biochemistry (Moscow). 2013.