The importance of age-specific gene expression.

Recently, I was asked to give a talk about stages of human development. This commentary is an expansion to that talk and concept. It also reviews various aspects of our present understandings of gene expression. Perhaps it is because I am a pediatrician that I automatically think about different stages in childhood development. Pediatricians test for major and minor motor development as well as intellectual and social development and chart these at each child's visit, taking note as these items progresses over time. Less thought and clarity are available about stages of development from puberty onward. However, over the millennium, as humans have evolved, new stages have been added to this repertoire. Of course, each stage has epigenetic control, and we are just beginning to gain insight into those processes (Chen et al., 2016). It appears that most gene expression is part of a pathway, and those pathways are different for different tissues and change over time during a lifetime of development. They are most definitely different for males and females (Khramtsova et al., 2023; Supekar et al., 2022). Some progress is being made at identifying the differences in gene expression in different tissues (Chen et al., 2016; Eraslan et al., 2022; Iwata et al., 2022; Jones et al., 2022; Liao et al., 2023; Liu & Zhang, 2022) and at different times in development (Ben Ezra et al., 2023; Loyfer et al., 2023). But in the long run, we would need to develop a useable catalog of these new insights regarding single cell expression, as well as a description of the proteins present in the extracellular fluids of each tissue. There may be differences between different ethnic groups (Liao et al., 2023; Xu et al., 2023; Zhang et al., 2023). Furthermore, there will be differences because of the transgenerational programing we know exists (Loyfer et al., 2023; Szyf, 2015), potentially creating important functional differences. Obviously, pioneers have begun to use an understanding of control of gene expression therapeutically already. The importance of these shifts with developmental age was recognized long ago in the progression from embryonic to fetal to adult hemoglobins where different genes turn on at different developmental stages in embryonic/fetal development, relating to differing affinities for oxygen. In many cases, there may be alternative splicing rather than differences in the genes that turn on with development (Leung et al., 2021). One can anticipate that there will be different parts of these pathways under different control (Gomez-Verjan et al., 2018). Most of these differences were likely to provide selective advantage for their carriers to have been maintained during the course of our evolution (Davison & Gurven, 2022). It has been determined that there are only around 22,000 human genes, but more than 200,000 proteins that are produced in the human body from those genes, suggesting alternative splicing makes different proteins for different functions at different ages of development (or in different tissues), and that this has become the “preferred” mode of protein production for that tissue, age, and sex in the course of human evolution. For much of modern molecular physiology, adult male tissues have been used for physiological and gene expression studies. However, to observe the variations during development and the female cyclic physiology (Talamanca et al., 2023), those male proteins do not reveal the true nature of our wonderfully complex human bodies (Barrio-Hernandez et al., 2023). As well there must be physiology differences in the response to various stresses (Poganik et al., 2023), various microbiomes, and types of illnesses, not to mention the remarkable interactions between all these tissues in the functioning body. There are over 400 different tissues in our bodies. Hard to believe but new tissues are still being found (Møllgård et al., 2023). When a catalog (an expansion of the human cell atlas) of tissue-specific, time in development-specific and biological sex-specific protein production is eventually available, it will hold many new surprises and insights, and shed light not only on ourselves, but also on other primate species and of course on evolutionary processes. Being an optimist, I would like to think that there would also be enormous opportunities for treating genetic disease when such a catalog is available. In other words, as we learn more about control of gene expression through the study of epigenetics and transgenerational effects (Gomez-Verjan et al., 2018; Radford et al., 2014; Szyf, 2015), we will gain insight into how to turn on and off genes from various stages and tissues and hence the proteins of a different age or different tissue. Theoretically, that could be much easier than our present form of gene therapy. This has already been accomplished in Escobar syndrome (caused by a pathogenic variant in one of the five genes of the embryonic neurotransmitter receptor) where failure to turn on the adult neuroreceptor occurs (Hoffmann et al., 2006). A drug was already available which has been used to treat myasthenia gravis and was found to turn on the adult gene in individuals with Escobar syndrome after birth (Michalk et al., 2008) who would otherwise die of pulmonary failure by 20 years of age. I do not even want to begin to think about potential ethical quagmires, for instance involved in prenatal diagnosis and prenatal therapy utilizing these alternative gene pathways, nor the physiology in LGBTQ+ individuals. However, I think it is important to set our sights high and anticipate that there will be many different levels of therapy for various situations. Mental health issues of course are likely to be different than inborn errors of metabolism although the brain and liver may use the same “read out” for a particular protein. We do not yet understand all the differences in control of the “read out” that produces identical proteins in different tissues. Nevertheless, I write this commentary to encourage “big picture” thinking and provide hope in this time of the endless stress of the pandemic. There are so many seemingly intractable childhood genetic disorders. And the fear of older people is that they will “lose their marbles” and control of their lives. We know from cancer that all the tissues in the body continue to go through genetic changes over a lifetime, often because pathogenic variants arise in specific tissues, but also they may occur because of transposable elements (small pieces of DNA that move from one location to another) (Gorbunova et al., 2021). How exciting to think there may develop targeted alternatives, not that I am encouraging we put these new resources to finding the fountain of youth, but rather aim for every individual to achieve a healthy, fulfilled life. Table 1 is a working list of the developmental stages of human beings extending the observations during childhood. Some of the early stages are fairly clear in their cut-off points, but during the course of aging, there may be a lot of variation between individuals. So early stages may need to be defined by weeks, by months during childhood, and by years from adolescence onward. Theoretically, each stage includes motor, intellectual, emotional, psychological, and physical development. Interestingly, there seem to be the onset of clusters of inherited diseases due to pathogenic variants at the onset of each of the proposed stages (see “Illness onset stages” column in Table 1), which helps to define when each of these stages are occurring. As more is learned, there will undoubtedly be adjustments to this table. Different tissues may require their own tables. Clearly, males and females deserve separate attention including the circadian and cyclic changes we know exist (Pitsawong et al., 2023; Talamanca et al., 2023). In other words, this is just a first attempt and I welcome any inputs or insights to enlarge this table in a useful way. I am particularly interested in the after-65 stage (Hall, 2005, 2013, 2020). When I was born, my life expectancy was 59 years. Because of public health measures such as clean water and immunization, I have gained an extra 30 years of life expectancy over my life thus far. This is an extra 30 years that no other generation has expected. Of course, there have been individuals who have lived into old age, way past the life expectancy for those born in their birth year. It is really this expectation to be able to live longer, and that leads to my interest in the older stage(s). Every hunter-gatherer or indigenous society has a Council of Elders who have a lifetime of experiences and their knowledge is said to turn into wisdom (crystalline thinking) (Brooks, 2022). Many of these Elders have lived past the life expectancy of their times. However, this present generation of older adults are like pioneers and explorers—with the expectation for the extra 30 years to test new boundaries and develop new abilities. Although the human brain has not changed in its outward appearance in 150,000 years, new brain/neural connections and abilities are likely to have developed. One can imagine that among a band of hunter-gatherers, if there was an older person who had lived through a famine or a war, their experiences could lead to survival of their band and their descendants at a later time! They know where to find food during a famine and what the techniques used by their adversaries were during a previous war (Davison & Gurven, 2022). Therefore, their children and grandchildren would be more likely to survive, and there will be a selective advantage for this growing older. It is well known that among hunter-gatherers, if there is a grandmother, the children are much more likely to survive since they are less at risk while mother is off gathering food and fuel (Hawkes, 2003). Similarly, with the major improvements of public health in developed countries, the water-borne diseases and infectious diseases that killed whole populations can now be prevented through the shared knowledge of science (Hall, 2020). So, what are the particular advantages of the last period of human development? And how do we recognize them, enhance them, use them, and celebrate them? We know that aging brings changes in memory, word access, and cognitive alterations as well as changes on MRI, including cell loss, decreasing gray matter, loss of inhibitory connections, faster processing (Barrio-Hernandez et al., 2023; van Blooijs et al., 2023) and new neuronal connections (pathways) (Cohen, 2005). In addition, there are changes in organelle function (Vardalaki et al., 2022) (such as in ribosome, mitochondria, lysosome, etc.) (Iwata et al., 2023; Stein et al., 2022). Apparently women start the aging process as measured by inflammation and formation of giant cells, earlier than men, but it moves more slowly than in men (Ben Ezra et al., 2023). It is well known in all cultures that women live longer than men (Hawkes, 2003). Cohen (2005) reflects on the positive changes in human brain function that lead to less concern with achievement and less ability to be on the cutting edge. He also notes there are improvements in ability to deal with the complex problems, to get the “big picture” and find solutions beyond the usual formal ones (Hall, 2020). There is an integration of subjectivity and objectivity, creating a gestalt of experiences from the past that recognizes patterns in the present. Looking at both sides at the same time allows for tolerance of ambiguity (Cohen, 2005). Aronson (2019) describe generativity, gratitude, generosity, and the value of human interactions that comes with age. Some describe it as wisdom from lived experiences. Older people seem to lack the snap judgments and hedonist behavior of youth. Over a lifetime reflection and cognitive reappraisal comes a wise rational approach some called generativity as well as increased spirituality (Zweig, 2021). It had been said for some time that one learns from the hard knocks of life, and becomes wise. It is certainly true for many people, but unfortunately, apparently not for all. So, is there a way in our socialized civilizations to enhance this process and all benefit from a combined experience of our lifetimes. Just to finish up, we need that catalog of tissue-specific, time in development-specific, and biological sex-specific gene expression, together with both transcriptional and proteomic approaches to single cell analogs. It will hopefully lead not only to new insights, but to new avenues of prevention and therapy as well. I am very grateful for the ongoing support from the BC Children's Hospital Foundation. The authors declare no conflicts of interest. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.