The Latest Rejuvenation Research Commentary on Relevant Papers

The "commentary on some recent theses" section is a regular feature of the Rejuvenation Research journal, penned by Aubrey de Grey and collaborators. Historically it has been behind a journal paywall, but it is presently open access - and in this day and age of organized copyright heretics who assemble online databases of papers normally locked away, it is ceasing to much matter whether or not journals maintain a paywall when it comes to access. The most recent commentary touches on a range of different topics; reading it all is recommended. The quoted material here relates to an interesting discovery regarding the senescence of astrocytes in the aging brain, which, as noted, offers the promise of effective near future treatments for a range of neurodegenerative conditions.

Of the seven strands of the SENS platform, the ablation of senescent cells (ApoptoSENS) has thus far made the most progress towards the clinic; drugs that selectively eliminate these toxic and superfluous cells are referred to as senolytics, and several are now undergoing or are soon to enter clinical trials. Recent evidence from preclinical work has indicated that the role of senescent cells in the aging process is remarkably significant, such that resolving this single form of damage yields dramatic benefits across the spectrum of age-related decline - simultaneously extending both lifespan and healthspan in mouse models.

Although the existence of a true senescent phenotype in postmitotic cells such as neurons is still unproven, its existence in their crucial support cells, the astrocytes, has been recognized since the beginning of this decade. A recent dissertation makes vital progress towards proving the clinical relevance of the phenomenon - laying the groundwork for the translational application of senolytics to major neurodegenerative diseases. Glutamate (together with aspartate) is the major excitatory neurotransmitter in the human brain, and dysfunctions of its handling are clearly associated with both acute and chronic neurological conditions. That such dysfunction is here shown to be an intrinsic consequence of physiologically realistic levels of astrocyte senescence leaves little doubt that a mechanistic connection must exist. In Alzheimer's disease specifically, it is notable that the loss of glutamate receptors in postmortem samples tracks both the brain's major excitatory pathways and also the very well-established progressive staging of the disease. These results are good news indeed!

Replacing intrinsically aged neurons without disrupting synaptic connectivity has always been accepted to be a daunting task, but astrocyte turnover - while low in healthy tissue - is a routine process following injury (albeit one that has side effects of its own when driven to excess in the context of chronic inflammation, although these appear somewhat treatable). Thus, depleting senescent astrocytes and so neutralizing their inflammatory effects may well automatically induce their replacement by healthy new cells; and even if not, stimulating that process is not an insurmountable challenge. At the very least, such a therapy should prevent further degeneration - and perhaps even create the conditions for the repair of pre-existing neuronal decline as well, especially since a subset of those astrocytes may be able to function as neural stem cells.

Link: https://doi.org/10.1089/rej.2018.2054

Comments

A tl;dr from reddit:

1 ~ "Characterizing Senescence in Astrocytes and its Effect on Neurons" - Glutamate (and aspartate) dysfunction is shown to be an intrinsic consequence of physiologically realistic levels of astrocyte senescence, so senescent cell ablation should have positive effects on neurodegenerative diseases.

2 ~ "Contribution of Adult Skeletal Muscle Stem Cells to the Regeneration and Lifelong Maintenance of Neuromuscular Junctions" - By identifying a crucial role for satellite cells in junction maintenance (complementing their known role in maintaining muscle per se), this thesis contributes an important new element to our understanding of the mechanisms underlying age-related infirmity, and reinforces the importance of developing methods to reverse satellite cell decline.

3 ~ "Investigation into Feasibility of Color and Texture Features for Automated Detection of Lymph Node Metastases in Histopathological Images" - This thesis develops software able to identify a range of carcinomas in lymphatic tissue samples, thereby reducing the need for other prior information to make an initial diagnosis, and potentially lowers medical costs by reducing the need for the involvement of a human expert.

4 ~ "Stem Cell Engineered Invariant Natural Killer T Cells for Cancer Immunotherapy" - In the context of cancer, iNKT cells have particular promise precisely because their function is largely agnostic to the specific antigens present - thus rendering immunoevasion less of a barrier to therapeutic efficacy - and because they are especially sensitive to the presence of the pro-inflammatory cytokines found ubiquitously in tumour stroma, which in sufficient concentrations can trigger a robust iNKT response absent any antigen-specific engagement at all. Since iNKT cells are relatively short-lived the source hematopoietic stem cells could in principle be genetically engineered to produce them in vivo not constitutively but rather in response to a bioorthogonal stimulus. Repeatedly producing fresh iNKT cells in vivo from inplanted HSCs would also avoid the problems of T cell exhaustion seen in CAR T cells expanded ex vivo.

5 ~ "Supramolecular Peptide Nanofibers for Active Immunotherapy" - Rather than expensively produce therapeutic antibodies to self molecules such as TNF alpha in bioreactors and then inject them into the body, it would be cheaper to create a vaccine against the self molecule so that a patient's body could produce its own antibodies. However vaccines raise both a B cell antibody response and a T cell response. The T cell response can go on to kill the cells producing the self molecule of interest. Using Supramolecular Peptide Nanofibers it is possible for the first time to create a vaccine that raises a B cell antibody response but not a T cell response.

6 ~ "Visualisation and Monitoring of Tumour-Mediated Immune Modulation in Primary Cancer and Premetastatic Niche" - An indium radioisotope tag has been developed for an exosome protein that cancers use to establish an imuno suppressed niche in a new tissue before metastasing there, laying the groundwork for methods to abolish such niches before metastasis can become established.

Posted by: Jim at February 23rd, 2018 7:33 AM

@Reason, will Rejuvenation Research be OA forever?

Posted by: Ariel at February 23rd, 2018 10:31 AM

@Ariel: No idea; the journal company has temporarily opened it in the past.

Posted by: Reason at February 23rd, 2018 12:45 PM

Sci-hub is the answer :)

Posted by: Steve Hill at February 23rd, 2018 6:14 PM

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