Before scientists and society began to think about how to slow aging and to prevent cancer, evolution has been creating its own models and mechanisms for millions of years, tuning them by adaptation to environmental stress and facilitating longevity, healthy aging and reduced cancer risk. Studies that have been conducted for more than 50 years at the Institute for Evolution at the University of Haifa have revealed unique characteristics of Spalax, a long-lived Mediterranean region solitary rodent living underground and challenged by numerous stressful situations. Spalax evolved distinctive mechanisms for combating environmental hypoxia, oxidative stress and has effective mechanisms to maintain DNA integrity. We are currently focusing on the molecular mechanisms of cellular senescence and maintaining non-permissive cancer microenvironment in Spalax

Cellular senescence and non-canonical SASP in Spalax

Senescent cells lose their ability to divide, inhibiting the propagation of mutations to the next cell generation in response to telomere shortening, DNA damage, or oncogenic stimulus. Notwithstanding the physiological role of senescence in preventing malignant transformation, senescent cells accumulate in damaged or aging tissues and are capable of influencing the surrounding cells through senescence-associated secretory phenotype (SASP). Canonical secretome of senescent cells comprises a specific pattern of inflammatory mediators and growth factors that may induce senescence in surrounding cells, an effect known as "bystander senescence". The accumulation of senescent cells leads to SASP amplification, which, in turn, modulates the surrounding tissues and causes the so-called "sterile inflammation", the microenvironment that supports most age-related pathologies, including malignant neoplasms.

Cellular senescence is not a ubiquitous example of antagonistic pleiotropy: the case of Spalax

We think that, unlike other mammalian species, cellular senescence in Spalax does not contribute to tumor promoting SASP remaining beneficial in old Spalax individuals by preventing chronic inflammatory response and malignant transformation.

Amani Odeh, PhD student (2016-2019); postdoctoral fellow at Karolinska Institutet, Stockholm, Sweden (2020-2021);

Dr. Amani Odeh is currently continuing her postdoctoral fellow in our laboratory and her main project is molecular mechanisms for the prevention of musculoskeletal aging in Spalax

Aging Cell, Volume 19, Issue 1 January 2020 acel.13045; Wiley Online Library

~Spalax fibroblasts undergo replicative senescence (RS) and etoposide‐induced senescence (EIS), evidenced by an increased activity of SA‐β‐Gal, growth arrest, and increased p21, p16, and p53 (Fig. A);

~ Yet, unlike mouse and human fibroblasts, Spalax senescent cells showed undetectable or decreased expression of the well‐known SASP factors (Fig. 2);

~High efficiency of DNA repair is responsible to suppression of inflammatory response in Spalax (Fig C);

~Downregulation of SASP secretion in Spalax senescent fibroblasts is associated, at list in part with suppression of IL1α cytokine response and inhibition of NF-kB translocation to the nuclei (Figs. D and E);

~Evaluation of SASP in ageing Spalax tissues confirmed downregulation of inflammatory‐related genes (Fig. F)

The evolution of the subterranean blind mole rat Spalax drove the development of anticancer abilities, presumably as a result of adaptation to environmental stress. The microenvironment in cancer is abnormal and characterized by low oxygen supply, hypercapnia, metabolic reprogramming, and irregular vasculature. These pathophysiological features of the Tumor Microenvironment create advantages for tumor growth. Hypoxia is Spalax natural milieu and its cells cope with oxidative stress and hypercapnia. We propose Spalax as a natural cancer-resistant organism in which pre-malignant or cancerous cells apparently do not receive assistance from adjacent stroma, and wherein tumors presumably would not be able to freely proliferate and metastasize.

Non-Permissive Cancer Microenvironment in Spalax: the Role of Adipose-Derived Stem Cells

Dr Anatolii Mamchur, postdoc (2015-2018); currently Dr. Anatolii is a Postdoctoral Associate at the University of Florida, Florida, USA

~In this report we demonstrated that the Adipose-derived Stem Cells (ADSC) of Spalax, have a low ability to migrate toward cancer cells and participate in intratumoral vasculogenesis.

~The lack of the basic property of ADSCs, namely recruitment by cancer cells, makes Spalax ADSCs unable to support the tumor progression.

~We found that the phenomenon of impaired migration in Spalax ADSCs is a consequence of sustained Myosin Like Chain (MLC) phosphorylation, leading to impaired polarization and deteriorated migration.

Treatment of Spalax ADSC by ROCK kinase inhibitor Y27632 resulted in the suppression of MLC phosphorylation, acquisition of actin polarization, and activation of motility and migration of Spalax ADSCs.

STEM CELLS 2018;36:1630–1642 www.StemCells.com ©AlphaMed Press 2018

The role of Myosin Light Chain (MLC) phosphorylation in impaired migration of Spalax ADSC

Apparently, along its evolution, Spalax acquired a mechanism that maintains stable phosphorylation of MLC, providing a constant contractile tone of the fast myosin ﬁbers. If this mechanism is extrapolated to the contractile activity of non-muscle Spalax cells (ADSCs, ﬁbroblasts, endothelial cells), sustained activation of MLC in stress ﬁbers can lead to impaired motility. These data shed light on the potential mechanism that Spalax uses to inhibit MSC migration to tumors, as well as preventing the intensive formation of pathological vessels in site of pathological wound.

Ongoing projects

Exploring the unique mechanisms of skeletal muscle aging and regeneration in the hypoxia-resistant and long-lived blind mole rat, Spalax: new insights into healthy aging

The progressive age-related loss of muscle mass and strength, termed sarcopenia, is one of the most serious consequences of aging. The etiology of sarcopenia is very complex and includes the replacement of fast twitch fibers with slow ones, a decrease in the pool of satellite cells (muscle stem cells) and their regenerative capacity and an increase in the level of inflammation with age.

Most studies of the molecular mechanisms of sarcopenia in mammals have been carried out using laboratory rodents susceptible to sarcopenia, and these studies provide insight into the pathogenesis of muscle loss with age.
However, among the vast diversity of species that live in different ecosystems in the wild and are forced to adapt to environmental stress, the physiology of skeletal muscles plays a vital role in ensuring survival. Unlike the rat and mice, Spalax maintains the ability to intensive digging throughout life (even in captivity) which requires high power of muscle contractions. According to preliminary data, fast fibers predominate in the structure of skeletal muscles of both young and old animals.

Spalax maintains the ability to intensive digging throughout life (even in captivity) which requires high power of muscle contractions
According to preliminary data, fast fibers predominate in the structure of skeletal muscles of both young and old animals.

Figure: Distribution of slow-twitch and fast-twitch fibers in trapezius muscles of young and old Spalax, and old mice;

(red: fast - twitch; green - slow-twitch fibers )

The main goal of the proposed project is to study the molecular and structural networks associated with the maintenance of the integrity, functional activity and energy metabolism of the skeletal muscle of Spalax throughout life. As part of this project, we are going to study the characteristics of skeletal muscle regeneration in Spalax (versus rat) in response to injury. These studies were not previously conducted and therefore are of both fundamental interest and clinical significance: new data will provide important information for elucidating specific genes and pathways that may be targeted to improve regeneration and suppress skeletal muscle wasting in the elderly.