On the road to "decrypting" aging

In revealing a new, fundamental molecular mechanism that functions in cells to preserve the integrity and function of the nucleus and regulates somatic as well as reproductive aging, researchers from the Institute of Molecular Biology and Biotechnology (IMBB) of the Technology and Research Foundation (ΙΤΕ) proceeded, through which they aim at the early diagnosis and early prevention, with precision medicine or personalized medicine methods, of the occurrence of neurodegenerative diseases and specific forms of cancer in humans .

Speaking to the Athens Agency and Ourania Moraitis, the president of ITE, and professor of the School of Medicine of the University of Crete, Nektarios Tavernarakis, characterized as one of the most fascinating mysteries of modern times biomedicine research, the understanding of the molecular basis of two diametrically opposed, fundamental phenomena in biology, which are none other than the "mortality of the body and the immortality of the so-called germ cell line", i.e. the cells of the reproductive system that ensure reproduction.

"The recent research of our laboratory at the Institute of Molecular Biology and Biotechnology (IMBB) of the Foundation for Technology and Research (ITE), the results of which are published in the prestigious international scientific journal Nature Aging, αποκάλυψε έναν νέο, θεμελιώδη μοριακό μηχανισμό που λειτουργεί στα κύτταρα για τη διαφύλαξη της ακεραιότητας και της λειτουργίας του πυρήνα, και ρυθμίζει τη σωματική καθώς και την αναπαραγωγική γήρανση. Η προοπτική της αποκάλυψης του μηχανισμού που είναι υπεύθυνος για αυτό τον έντονα ιδιοσυγκρασιακό χαρακτήρα των κυτταρικών τύπων, μέσα στον ίδιο οργανισμό, αποτέλεσε για εμάς ισχυρό κίνητρο για να προσπαθήσουμε να δώσουμε απάντηση σ' αυτό το σημαντικό ερώτημα» Reported Mr. Tavernarakis who added that, based on this, at IMBB they decided to focus on nuclear morphology, which deteriorates in somatic cells during aging, while, in contrast, remains unchanged in the stem cell line.

"Our hypothesis was that a highly efficient homeostatic mechanism maintains the structure of the germ cell nucleus, while failing to do the same in the body's somatic cells during aging. We were surprised to find that a special autophagy process, nucleophagy, is a central factor in maintaining the architecture of the nucleus, recycling nuclear material, while limiting the increase in nucleolus size observed during aging. Nucleophagy is a process that repairs damage that occurs in the nucleus of the cell, which contains all the genetic information, i.e. DNA" pointed out Mr. Tanvernarakis, clarifying that "in studies done on experimental animals, in which nucleophagy was suppressed, we observed phenomena of premature aging and reduced reproductive capacity, while on the contrary, genetic or pharmacological interventions to enhance nucleophagy, making it more efficient, have the effect of extending the lifespan of the organization".

With this as a basis, as the president of ITE pointed out, it is of particular interest to researchers that "nucleophagy itself is regulated by signaling pathways and interventions, such as those of insulin and caloric restriction, that determine lifespan in many different organisms, from nematodes to mammals" and how "this highlights the pivotal position of nucleophagy, as a point of convergence of molecular and cellular processes affecting aging."

The study, however, brought to light yet another important knowledge related to the genes that affect the process of repairing damage in the cell nucleus and are intertwined with carcinogenesis, that is, the appearance of cancer in humans.

"It is particularly important that people with cancers of the reproductive organs, such as ovarian cancer in women, show mutations in these genes. Essentially, this research connects, for the first time, two biological phenomena which were considered completely different. On the one hand, the repair of damage to the cell nucleus, nucleophagy, and on the other hand, aging and carcinogenesis" said Mr. Tavernarakis, explaining that specific genes were identified that jointly regulate these processes.

"We hope that this new knowledge will lead to the early diagnosis and timely prevention, with methods of precision medicine or personalized medicine, of the occurrence of neurodegenerative diseases and specific forms of cancer in humans" emphasized the president of ITE, who stated that "the results of the research highlight nucleophagy as a central molecular mechanism through which the long-term maintenance of nuclear architecture and homeostasis is ensured. These findings are expected to be used to treat diseases, which are characterized by the collapse of the architecture of the core, but also human infertility". As Mr. Tavernarakis said, the published study is the result of a five-year research effort, which is still ongoing as, apart from being a very interesting biological phenomenon, as he pointed out, aging is a field of intense research activity, with laboratories and biomedical institutes throughout the world to study the molecular and cellular mechanisms responsible for aging itself and its consequences for human health.

"Our own research at the Laboratory of Neurogenetics and Aging of the Institute of Molecular Biology and Biotechnology of ITE focuses on the study of the molecular mechanisms that govern the function and pathophysiology of the nervous system. As experimental material, we mainly use the nematode Caenorhabditis elegans, and the research goals of our laboratory are oriented in three main directions. The first concerns the evolution of aging, not only of humans but of all living organisms.

Η δεύτερη είναι η μελέτη του νευροεκφυλισμού που ασχολείται με νοσήματα όπως το Alzheimer' s και το Parkinson' s. Η τρίτη σχετίζεται με τη λειτουργία του νευρικού συστήματος, και συγκεκριμένα με το πώς μπορεί ο οργανισμός να αποθηκεύει και να ανακαλεί μια πληροφορία (μνήμη και learning)» ανέφερε ο κ. Ταβερναράκης, ο οποίος επισήμανε ότι «με τις επιστημονικές του μελέτες, το εργαστήριο έχει συμβάλει σημαντικά στην κατανόηση των μηχανισμών νευροεκφυλισμού, μνήμης και μάθησης, καθώς και της γήρανσης», while also "has contributed to the development of innovative experimental tools and methods for the study of the nervous system and cell biology."

As for the main goal of the Laboratory, as mentioned by the president of ITE, it is for the results of our research to expand the understanding of neurodegeneration related to aging and to generate new knowledge about human health and quality of life.

New tools boost research

Επιχειρώντας αυτό το «ταξίδι στο άγνωστο» που είναι η κατανόηση του φαινομένου της γήρανσης και η λειτουργία του νευρικού συστήματος, οι ερευνητές του ΙΜΒΒ απέκτησαν πρόσφατα, με χρηματοδότηση από ευρωπαϊκές και εθνικές πηγές, νέα εργαλεία προκειμένου να ενισχύσουν την έρευνά τους. Δύο εξελιγμένα συστήματα μικροσκοπίας υπερυψηλής ανάλυσης, μοναδικά στην Greece, που είναι κατάλληλα για πειράματα απεικόνισης ζωντανών και μονιμοποιημένων δειγμάτων, που απαιτούν ανίχνευση δομικών λεπτομερειών εντός του κυττάρου και των κυτταρικών οργανιδίων, καθώς και παρακολούθηση βιολογικών διαδικασιών, σε πραγματικό χρόνο, με υψηλή ταχύτητα απεικόνισης.

It is an ultra-high-resolution microscopy platform capable of imaging subcellular and sub-organ structures in live specimens in real-time, with 3D image reconstruction and multispectral analysis. "Using modern Structured Illumination Microscopy (SIM2) techniques, this system enables imaging beyond the diffraction limit of conventional microscopy, doubling conventional SIM resolution and achieving image reconstruction taken under particularly demanding conditions" said the president of ITE adding that «παράλληλα εφαρμόζει λειτουργίες βελτίωσης ταχύτητας εξασφαλίζοντας γρήγορη ταχύτητα απεικόνισης για καταγραφή εξαιρετικά δυναμικών διαδικασιών, σε εξαιρετική ανάλυση και στις τρεις διασtrends (3D)».

In this way, better sub-organ structure discrimination is achieved, with image resolution, as well as high speed during imaging, without the need for special sample preparation and with minimal exposure of the sample. Furthermore, όπως τόνισε, το σύστημα επιτρέπει τον ακριβή εντοπισμό μεμονωμένων μορίων με χρήση Μικροσκοπίας Εντοπισμού Μορίου (SMLM), με τεχνικές για πλευρική ανάλυση (xy), ενώ η χρήση κατάλληλων πηγών λέιζερ υψηλής ισχύος καθιστούν εφικτή την κατάλληλη επιλογή χρώσεων και φθοριζουσών πρωτεϊνών και παρέχουν δυνατότητα ανίχνευσης και απεικόνισης δύο διαφορετικών καναλιών φθορισμού, σχεδόν ταυτόχρονα.

In addition to the ultra-high-resolution microscopy platform, researchers at the Institute now have a high-sensitivity confocal microscope suitable for complex imaging experiments on live and fixed samples. This innovative system offers the possibility of monitoring dynamic processes in live samples with high imaging speed and ultra-high image resolution quality, with the use of a special detector that allows the collection of more information at the focal level, yielding quantitative super-resolution results.

"By exploiting additional functional capabilities of the system, the high-resolution capability can be combined with the collection of more information in less time, for real-time monitoring of intracellular processes" concluded Mr. Tavernarakis.

Source: RES-EAP