A parthenogenetic quasi-program causes teratoma-like tumors during aging in wild-type C. elegans

Abstract

A long-standing belief is that aging (senescence) is the result of stochastic damage accumulation. Alternatively, senescent pathology may also result from late-life, wild-type gene action (i.e., antagonistic pleiotropy, as argued by Williams) leading to non-adaptive run-on of developmental programs (or quasi-programs) (as suggested more recently by Blagosklonny). In this study, we use existing and new data to show how uterine tumors, a prominent form of senescent pathology in the nematode Caenorhabditis elegans, likely result from quasi-programs. Such tumors develop from unfertilized oocytes which enter the uterus and become hypertrophic and replete with endoreduplicated chromatin masses. Tumor formation begins with ovulation of unfertilized oocytes immediately after exhaustion of sperm stocks. We show that the timing of this transition between program and quasi-program (i.e., the onset of senescence), and the onset of tumor formation, depends upon the timing of sperm depletion. We identify homology between uterine tumors and mammalian ovarian teratomas, which both develop from oocytes that fail to mature after meiosis I. In teratomas, futile activation of developmental programs leads to the formation of differentiated structures within the tumor. We report that older uterine tumors express markers of later embryogenesis, consistent with teratoma-like activation of developmental programs. We also present evidence of coupling of distal gonad atrophy to oocyte hypertrophy. This study shows how the Williams Blagosklonny model can provide a mechanistic explanation of this component of C. elegans aging. It also suggests etiological similarity between teratoma and some forms of senescent pathology, insofar as both are caused by quasi-programs.

Does senescence promote fitness in Caenorhabditis elegans by causing death?

“…Arguably, a shortcoming of this definition is that it is ambiguous as to whether or not programmed here implies a process that contributes to fitness, particularly since the word "programmed" implies purpose ( Austad, 2004 ). To clarify this, the term quasi-programmed was introduced, to denote development-like processes that promote fitness in early life that run on in later life and promote senescence but not fitness ( Blagosklonny, 2006 ); a good example of this in C. elegans is uterine tumour formation ( Wang et al, 2018 ). To reduce ambiguity in this review, we refer to adaptive and non-adaptive programmed aging as programmed and quasi-programmed, respectively.…”

Monsters in the uterus: teratoma-like tumors in senescent C. elegans result from a parthenogenetic quasi-program

“…This simple pathobiology provides some useful lessons, for example about theories of aging [ 5 ]. Here the wild-type daf-2 insulin/IGF-1 receptor gene is exhibiting antagonistic pleiotropy (AP), promoting development first of germline and then of tumors.…”

“…Ovarian teratomas form sacs containing multiple tissues (skin, cartilage, hair). Both ovarian teratomas and worm uterine tumors result from embryogenetic quasi-programs in abnormal diploid cells resulting from a failure of meiosis II [ 5 ]. Notably, older C. elegans uterine tumors show expression of markers of later embryogenesis, though no actual differentiated cells, hence are teratoma-like [ 5 ].…”

The mesoSPIM initiative: open-source light-sheet microscopes for imaging cleared tissue

“…For example, the openSPIM project is highly successful as a tool to train microscopists on how to build and use a light-sheet microscope. However, only a small fraction [16][17][18][19][20][21][22] With the mesoSPIM initiative, we hope to provide a mesoscopic imaging instrument for cleared tissue en par or better than existing options. The setup is thus suitable for research groups or imaging facilities in search of alternatives to the existing palette of commercial instruments.…”