The daily habits of an animal may indicate their lifespan by the age of the midlife stage.

It is the disturbing end of a new study backed by the Knight Initiative of Brain Resilience at the Wu Tsai Neurosciences Institute of Stanford where researchers placed scores of short-lived fish inside continuous, lifelong surveillance to investigate the connection between behavior and aging.

Growth of individual fish in the markedly different ways, although the genetics were similar and the environment was closely monitored. By the time the animals grew up to their youthfulness, those differences had already been shown in their swimming and resting habits–and were so great as to determine whether a fish would in the end live to a long or brief existence.

Although the study was in the case of fish, the results suggest that the ability to record minor, daily behaviors such as movement and sleep, which wearable devices now capture daily, might provide insights into the process of aging in humans.

It was published in Science on March 12, 2016, and was the result of a study headed by Neuro postdoctoral students Claire Bedbrook and Ravi Nath at Wu Tsai Neuro. The study was an extension of a Knight Initiative-funded project between the Stanford labs of geneticist Anne Brunet and bioengineer Karl Deisseroth, who were the senior authors of the study.

How to observe the process of aging?

In the majority of aging studies, the comparison is made between groups of young animals and groups of old ones. Though enlightening, those snapshots obscure the way ageing occurs in individuals over a period of time, and the way disparities among individuals occur.

Bedbrook and Nath were interested in what could be uncovered by observing aging throughout a lifespan in the entire adult lives. The aging trajectories of even animals of the same species, raised under comparable conditions, can be radically different, and they may greatly differ in length of life. The researchers posed the question whether in natural behavior the beginnings and the way of divergence of those individual paths can be found out.

The making of that question experimentally possible was done by the African turquoise killifish. Being one of the shortest-lived vertebrates examined in the lab with a typical lifespan of four to eight months, it still possesses certain important biological similarities with other longer-lived organisms, such as humans, such as a sophisticated brain.

This study is based on the Brunet lab pioneering the design of a killifish model to study aging, and the foundation of this research was the first to continuously follow individual vertebrates (day and night), and through their entire adult lives.

Bedbrook and Nath and their colleagues designed an automated apparatus where individual fish were kept in separate tanks which were monitored by a camera. Similar to a scientific version of The Truman Show, where the whole life of a man is filmed straight through, the installation filmed each and every moment of the animals lives. Overall, they trailed 81 fish and produced billions of video frames.

Based on those recordings the researchers extracted specific data concerning the posture, speed, rest and movement of the animals and were able to identify 100 different behavioral syllables or short recurrent actions that are the elementary building blocks of the movement and rest of a fish.

According to Brunet, the Michele and Timothy Barakett Professor of Genetics at Stanford Medicine, behavior is a marvelously coordinated display, a report on what is going on in the brain and in the body. Molecular markers are the crucial components, though they are mere slices of biology. Through behavior you observe the entire organism, incessantly and without any form of invasion.

Now having this life-long record of behavior, the researchers were able to start to ask another group of questions: When do animals begin to age differently? What is different about those paths at the beginning? And, can behavior in itself determine the length of lifespan of a person?

The indicators of an animal lifespan

The discovery of the early divergence in individual aging paths was indeed one of the most unexpected discoveries of the team. The researchers then tracked each fish throughout its lifespan and then clumped the animals according to the amount of time they eventually spent alive and then traced back to the point of behavioral distinction. They discovered at a young age (70 to 100 days of age) fish which would further survive shorter or longer lives were already acting differently.

Among the most obvious distinctions, there were sleep. Young adults had fish which lived shorter lives, were more likely to sleep at night, and more and more during the day. On the contrary, fish which survived longer in life tended to sleep at night.

But it was not sleep alone which signalled. Fish on paths to a longer life also swam more vigorously and faster when they ran about the tank–a gauge of spontaneous movement which, in other species, has also been found to be associated with longevity. Their nocturnal activities were also less.

Most importantly, such differences in behavior were not merely descriptive but predictive. The researchers demonstrated that only a few days of behavioral data of middle-aged fish were sufficient to predict lifetime with the aid of machine learning models. According to Bedbrook, behavioral changes at a very young age are informing us of future health, as well as, future lifespan.

Aging unfolds in steps

Their observations, also, showed that aging, at any rate in killifish, was not a gradual gradual drift. The majority of the fish passed through two or six fast behavior changes, with only a few days each, and then longer, more stable periods of several weeks. Notably, fish would develop in a certain sequence, as opposed to alternating between them.

“It was a slow process,” Bedbrook said, “of getting old. Rather animals are stable over a long period and then they change rapidly into a new level. The fact that this staged architecture can be seen as a result of unchanged behavior itself was among the most thrilling things we have discovered. This progressive trend follows the emerging evidence of human studies, such as the discovery that molecular characteristics of aging vary in waves, particularly in midlife and old age. The killifish results provide us with a behavioral perspective of the same thing.”

The scientists speculate that a life cycle of relative stability interrupted by short intervals of intense change might have been one of the processes of aging. It is more of a Jenga tower, where you can remove a lot of blocks without much impact, until you make one change that requires a re-organisation to take place, which will force a sudden re-organisation, than a gradual downhill slide.

The authors also compared the activity of genes in eight organs of adult fish at a time when behavior was predictive of future lifespan. Instead of studying specific genes, they sought concerted alterations between clusters of genes that collaborate in common biological activities.

The most distinguishable differences were in the liver, where those genes that played a role in protein synthesis and cellular homeostasis were more expressed in fish that took shorter aging pathways. These results provided a molecular clue that the internal biology of the animals in question is also being altered with the changing behavioral pattern during their growth.

Behavior reflects fresh perspective on old age

According to Nath, “behavior is a very sensitive measure of aging. One can observe two animals of the same chronological age and can know by the mere behavior of the animals that they are aging very differently.”

The sensitivity is manifested in most spheres of everyday life, and sleep became a significant indicator of the way the aging process was being experienced. Sleep quality and sleep-wake cycles tend to impair as an individual ages, and these alterations have been associated with age-related cognitive decline and neurodegenerative disease in human beings. Nath also wants to inquire if it is possible to manipulate sleep to achieve healthier aging, and whether it is possible to change the aging process of individuals by acting early before they start to decline.

Another goal of the team is to test the possibilities of modifying aging paths with the use of specific interventions, such as diet modification, and also, genetic alterations that can potentially affect the rate at which aging will occur.

In the case of Bedbrook, the killifish research presents the possibility of exploration further on the subject of what motivates changes in transition during the aging process and the possibility to delay, prevent, or reverse changes in aging. She further takes interest in taking the experimental system further towards more naturalistic environments where animals are given the opportunity to socialize and live in richer environments closer to the real world.

Now, she said, “we can map the process of aging in a vertebrate on a continuous basis. As wearables and long-term tracking become a reality in human beings, I am interested to learn whether the same principles, namely: early predictors, staged aging, divergent trajectories, will also apply in human beings.”

The other significant frontier is the brain itself. The lab created by Deisseroth works on equipment to record the neural activity during extended durations of time, and, as a result, one can trace the variations of neural activity and the aging trajectory of the same animals. Such experiments may show whether the brain reflects aging in the rest of the body or is more directly involved in determining the rate of the aging process.

Both Bedbrook and Nath will proceed with answering these questions as they start their individual laboratories at Princeton University this July, carrying the equipment and concepts that were created at Stanford to the next level in their studies.

Ultimately, it is hoped that such a resolution of aging will explain why aging is so diverse, and will guide to emerging strategies of healthy aging.

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