Regeneration leads to global tissue rejuvenation in aging sexual planarians

Background:

Why we age is a question that has haunted the human psyche for, well, ages. But as fundamental as aging is for humans, there are some species – planarian flatworms among them – that appear, at least initially, to operate by a different set of rules. Despite their apparent simplicity, planarians have an incredible capacity to regenerate from damage, and unlike in mammals [1], this ability doesn’t appear to decline with time [2]. A beheaded worm simply grows a new head; a worm split in two will become two new worms. Cycles of damage and regeneration can repeat in perpetuity, leading some of their admirers to call these worms immortal [2].

An immortal worm might seem like an odd choice to study aging. But through diligent and patient observation of one such species, Schmidtea mediterranea, the authors found that sometimes they do age. Most planarian research has focused on an asexual strain of S. mediterranea, which reproduces by tearing in half, but another strain, which exclusively reproduces sexually, eventually starts showing age-related changes in physiological functions. And, most intriguingly, forcing an old worm to regenerate reverses those changes.

A species that ages under some conditions, but which can reverse most of the effects of age through regeneration, could be an incredible model to answer big biological questions about the fundamental processes of aging. Here, the authors begin to tackle that very big problem by starting with a smaller question: what does aging look like in a worm that can live forever?

 

Key results:

S. mediterranea get old

The authors’ first clue that flatworms age came from their eyespots, two googly-eye-like clusters of pigment cells on the top of the head. Eyespots are usually symmetrical, but the authors noticed that some of the worms had extra pigment cells or entire extra eyespots. Disordered eyespots appeared more and more frequently as the animals grew older, over the course of six months to five years.

The effects of aging aren’t limited to the eyespots, but extend to other critical physiological functions. By measuring the percentage of egg capsules that hatch into living worms, the authors found that the animals’ fertility decreased about fourfold from the 200-day mark to the 600-day mark. The worms also moved around less as they grew older, a relatable phenotype for many humans.

 

Regeneration resets the clock

Intriguingly, forcing the worms to regenerate reverted the effects of aging. Cut off the head of an old worm with disordered eyespots, and in twenty days it’ll grow a new head – with young-looking, symmetrical eyespots. Regeneration also rescued the effects of aging on fertility and movement; old worms that were cut into fragments regenerated into individuals which were as fertile and mobile as their youthful compatriots.

 

Age-induced transcriptional changes are reversed by regeneration

To explore how changes in gene expression might explain these age-induced effects, the authors did single-cell RNA sequencing of young, old, and regenerated planarian heads. By comparing their results to earlier single-cell data from an asexual strain of S. mediterranea [3] [4] [5], they categorized their data into specific cell types. They then looked for age-related changes in the proportions of these cell types. Older planarians have a lower proportion of some subtypes of neurons and muscle cells. On the other hand, the percentage of certain types of stem cells actually increased – a surprising result, since many of the effects of mammalian aging have been tied to reduced adult stem cell number or function.

All of these changes in tissue composition, though, were reversed back to youthful proportions in the regenerated tissue of old animals. Additionally, the transcriptome of regenerated tissue was overall much more similar to young tissue than old tissue, with most of the age-related transcriptional changes reverting to a young-like state.

The RNA sequencing dataset hints that some of the signaling pathways that change with age in other organisms, like insulin and TOR signaling [6], appear to show similar changes in S. mediterranea. However, figuring out the specific molecular mechanisms behind aging (and de-aging) in this system will require lots of further research. That said, this work is an important step forward in understanding why organisms age, and how – at least for the unassuming, immortal flatworm – those processes can be reversed.

 

Why I chose this preprint:

This preprint doesn’t answer all of the questions that it raises, but I think it’s a fascinating and important read for two reasons. First of all, it tackles an extremely interesting question – how organisms age – in a surprisingly well-suited model system. The regenerative abilities of planarians have been known for a long time, but as a relative newcomer to the model, they’re astounding, challenging my assumptions about the limits of biology. Secondly, by establishing solid descriptive biology about sexual planarian aging, and by generating a transcriptome for sexual planarians (most prior planarian transcriptomes used the asexual strain), the authors have set up a very useful knowledge base for future research on aging.

 

Questions for the authors:

• Do you think that regenerated tissues reset the clock for non-regenerated tissues? When you remove half the head, the old eye doesn’t recover a young phenotype, but some of the phenotypes you look at (especially motility) seem like they’d require whole-body rejuvenation.
• Relatedly, did you consider single-cell sequencing the whole body? What motivated your decision to sequence just heads?
• Given that these age-related changes happen over such a long time, what first tipped you off that the variability you saw might correlate with age? What was it like planning and carrying out individual experiments that, by their nature, spanned years?

 

References:

1. Sousounis K, Baddour JA & Tsonis PA. Aging and regeneration in vertebrates. Curr Top Dev Biol 108, 217-246, doi:10.1016/B978-0-12-391498-9.00008-5 (2014).
2. Elliot SA & Alvarado AS. The history and enduring contributions of planarians to the study of animal regeneration. Wiley Interdiscip Rev Dev Biol 2(3), 301-326, doi: 10.1002/wdev.82 (2012).
3. Fincher, C. T., Wurtzel, O., de Hoog, T., Kravarik, K. M. & Reddien, P. W. Cell type transcriptome atlas for the planarian Schmidtea mediterranea. Science 360, doi:10.1126/science.aaq1736 (2018).
4. Plass, M. et al. Cell type atlas and lineage tree of a whole complex animal by single-cell transcriptomics. Science 360, doi:10.1126/science.aaq1723 (2018).
5. van Wolfswinkel, J. C., Wagner, D. E. & Reddien, P. W. Single-cell analysis reveals functionally distinct classes within the planarian stem cell compartment. Cell Stem Cell 15, 326-339, doi:10.1016/j.stem.2014.06.007 (2014).
6. Partridge L, Alic N, Bjedov N, Piper MDW. Ageing in Drosophila: the role of the insulin/Igf and TOR signalling network. Exp Gerontol 46(5), 376-381, doi: 10.1016/j.exger.2010.09.003 (2011).

Tags: aging, flatworm, planarian, regeneration, transcriptomics

doi: https://doi.org/10.1242/prelights.35033

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