Imagine being told today that a disease could be cured through magic. It's unlikely that we would readily accept such a claim. Our scepticism stems from the vast reservoir of knowledge and research we've amassed about diseases, allowing us to identify their root causes. 

However, if we rewind time, we'd find that the early human perspective on death and disease was far from considering them natural [1]. Over time, we've shifted from blaming supernatural causes for diseases to understanding the significance of self-care and protection, particularly as we age, knowing its role in primary life-threatening conditions. 

This change didn't occur abruptly; it was a gradual process driven by researchers who pieced together insights from various discoveries and observations. Let’s delve into the key breakthroughs that have moulded our comprehension of health and illnesses.

The Beginnings: From Humors to Cells

During the 5th century BCE, moving beyond supernatural concepts, humans began formulating theories, such as the four humors, as a result of their observations of various bodily fluids. This theory of humoralism posited that a person's temperament was influenced by four key bodily fluids: blood, yellow bile, black bile, and phlegm. Imbalances in these fluids were believed to result in specific illnesses, depending on whether there was an excess or deficiency of particular humors [2].

 In 1665, Robert Hooke's revolutionary microscope observations brought to light a previously unseen realm – the intricate world of cells within cork [3]. This ground-breaking revelation shattered prevailing notions of homogeneity and ignited a fervent scientific inquisitiveness.

Around 1674, Antonie van Leeuwenhoek revolutionized microbiology by meticulously studying microscopic specimens, revealing hidden microcosms of life. He adeptly isolated protozoa and bacteria, measuring their dimensions, and in 1676, he observed the first bacteria known to man in water. In 1677, another significant breakthrough occurred as Antonie van Leeuwenhoek and his colleagues documented spermatozoa in insects, dogs, and humans [3].

In that era, these findings were genuinely surprising to researchers, who were primarily focused on identifying microstructures rather than understanding their functions.

Unlocking Discoveries, Defining Roles

Upon observing numerous microstructures and assembling them, the investigation of the microscopic realm sparked a cellular revolution that fundamentally transformed our perception of life, encompassing pivotal moments such as the formulation of the cell theory, breakthrough identification of DNA, and revelation of intricate organelle functions, all contributing to an unparalleled leap in our grasp of life's foundational elements during the 19th century.

IMAGE - \ageing-research\exponential-decrease-in-size-of-cell-components-discovered.jpg

Exponential decrease in size of cell components discovery

Bacteria

Around 1828, Ehrenberg introduced the terms "bakterium" and "bakteria," stemming from the Greek "βακτηριον," meaning small stick [4], which is how they appeared. The identification was also the foundation for other research like Robert Koch's discovery of disease-causing Mycobacterium tuberculosis, eventually leading to the development of an attempt at vaccine therapy called tuberculin in 1890, derived from bacteria [5].

Cells

While the discovery of cells dates back to 1665 [3], Rudolf Virchow's 1858 assertion that "cells arise from pre-existing cells" significantly advanced our understanding [6]. This declaration revolutionized our perception of cells as fundamental entities, playing a pivotal role in shaping the trajectory of biological knowledge. It unveiled the concept of diverse bodily forms originating from a single cell and clarified the fundamental principles governing the functionality of living systems.

DNA

As cells gained prominence, attention shifted to their intricate components. In 1869, Friedrich Miescher revealed a mysterious substance in cell nuclei, later identified as DNA - the genetic guide of life. Miescher's finding initiated genetics, elucidating the blueprint governing inheritance, evolution, and diversity, with formal recognition evolving through contributions by scientists like Watson and Crick in 1953 [7].

Mitochondria

In 1857, these energy-producing powerhouses were discovered and subsequently acknowledged as the site of cellular respiration, where nutrients are converted into energy through oxidative processes. The function of mitochondria received clarity with Richard Altman's research in 1885 [8].

Ribosomes

The 1950s witnessed the identification of ribosomes, the cellular machinery pivotal for synthesizing proteins. These intricate structures serve as the linchpin connecting genetic information encoded in DNA to the production of functional proteins, a revelation that unfolded through relentless research and exploration in the following decades [9]. 

As our understanding evolved, additional structures like plasmids, telomeres, senescent cells, and stem cells came to light, unveiling the central role of cellular damage in disease, while our comprehension of cell functions also illuminated the influence of ageing on their gradual slowdown and eventual deterioration. With advancing age, cells become progressively weaker, contributing to the accumulation of damage.

Unlocking the Immune System's Secrets

Armed with this knowledge, researchers explored practical applications for these intricate bodily structures. As they delved into component functions, a key realization emerged: just as each structural aspect differs, so does each human body. The immune system's role in disease is notably influenced by individual variations.

The captivating journey into immunology began in 1796 with Edward Jenner's ground-breaking first vaccine [10], a turning point in medical history. It showcased the immune response's power against pathogens, fueling exploration of innate and adaptive immunity. Innate immunity, with physical and chemical defenses, is the initial barrier against invaders. Adaptive immunity, a more intricate strategy, involves specialized cells and molecules, including T-cells with distinct subsets. Helper T-cells orchestrate immune responses, while cytotoxic T-cells directly target infected cells.

Around 1911, Thomas Hunt Morgan revealed genetic foundations of immunity through chromosome-linked gene research [11]. Alexander Fleming's 1928 discovery of penicillin, the first antibiotic, shed light on genetic basis of immune responses [12]. Genetic variations influence disease susceptibility and treatment responses. 

It was well understood that genetic variations influence disease susceptibility and treatment responses. Overtime, the thymus, a vital immune organ, gained prominence for T-cell maturation, bridging genetics, cell development, and immune functionality. This journey underscores immunology's complexity and its impact on human health.

Thymus: A Late Revelation with Profound Implications

Throughout the 20th century, our understanding of the thymus's crucial role in the immune system and T-cell development has grown significantly, especially in the 1961 [13]. The thymus's journey from a mysterious gland with elusive functions to a pivotal immune organ stands as a testament to unwavering scientific dedication. Its acknowledgment arrived belatedly but carried profound implications. Investigating its connection to ageing and immunity uncovered a thought-provoking reality – its gradual decline with time has a direct impact on immune system functionality. 

However, the effects extend beyond immunity, exerting influence over various dimensions of overall health. This delayed revelation underscored the intricate interplay between bodily systems, emphasizing the importance of comprehensively grasping every facet of our biology to promote holistic well-being. Thus, the thymus emerged as a key determinant of the immune system's functionality.

Extracellular Vesicles: Tiny Particles with Tremendous Potential

In 1940, extracellular vesicles (EVs) were first uncovered, subsequently emerging as transformative players in ageing research, revealing their role as Very Important Particles (VIPs) governing cell communication [14]. These minute molecular carriers facilitate intricate information exchange, orchestrating a network regulating diverse physiological processes, including those tied to ageing. Particularly within the immune system context, EVs hold promise for advancing immunotherapy. Their potential in ageing-related studies and treatments is striking. 

EVs can deliver bioactive substances, precisely targeting interventions. In immunotherapy, they might carry immune-modulating agents or antigens, amplifying immunity against age-linked illnesses. Moreover, they offer a less invasive substitute for traditional therapies, curbing potential side effects. Challenges persist amid the excitement, requiring detailed exploration of EV cargo, biogenesis, and mechanisms. Standardizing isolation and analysis approaches remains an obstacle for consistency across studies. 

Nevertheless, as insights into these minute couriers' potential to reshape ageing's immune landscape grow, innovative strategies to harness their potential for enhanced health and longevity take form.

Conclusion

As we examine the astonishing progression of discoveries in ageing research, it becomes evident that we have come a long way from ancient beliefs in humors to understanding and treating the smallest building blocks of life. From the microscope's humble beginnings to uncovering the intricacies of DNA, stem cells, and extracellular vesicles, each step has paved the way for targeted and precise interventions against age-related ailments. 

With the exponential growth in ageing research, the future of ageing research holds promises we could only have imagined before. The journey is far from over, and as we continue to unlock the mysteries of life, we may eventually conquer the enigma of ageing itself.

Blog written by Sanjana Gajbhiye.

References

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5. “Historical Perspectives Centennial: Koch’s Discovery of the Tubercle Bacillus ,” Morbidity and Mortality Weekly Report, 1982.

6. “Cell Theory | Definition, History, Importance, Scientists, First Proposed, & Facts | Britannica.” In Encyclopædia Britannica, 2023.

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8.  “Mitochondrion.” Wikipedia. August 5, 2023.

9. Genome.gov. “Ribosome,” 2023.

10. Riedel, Stefan. “Edward Jenner and the History of Smallpox and Vaccination.” Baylor University Medical Center Proceedings 18, no. 1 (January 1, 2005): 21–25.

11. Asude Durmaz, Emin Karaca, Urszula Demkow, Gokce Toruner, Jacqueline Schoumans, and Ozgur Cogulu. “Evolution of Genetic Techniques: Past, Present, and Beyond.” BioMed Research International 2015 (January 1, 2015): 1–7.

12. Gaynes, Robert P. “The Discovery of Penicillin—New Insights after More than 75 Years of Clinical Use.” Emerging Infectious Diseases 23, no. 5 (May 1, 2017): 849–53. 

13. Thapa, Puspa, and Donna L Farber. “The Role of the Thymus in the Immune Response.” Thoracic Surgery Clinics 29, no. 2 (May 1, 2019): 123–31.

14. Breeden, Dan. “Extracellular Vesicles as ‘Very Important Particles’ (VIPs) in Aging.” @LifeboatHQ, February 28, 2023.

15. Cordeiro, José, and David Wood. “The Death of Death.” SpringerLink, 2023.