SCIENCE science.org 12 NOVEMBER 2021 • VOL 374 ISSUE 6569 825genetic mosaicism (whereby cells have dif-
ferent mutational profiles) and transcrip-
tomic heterogeneity were observed in aged
mice ( 9 ). Relaxed selection is manifested as
a reduction in the strength of natural selec-
tion on particular traits that were formerly
important. Short-lived killifish face variable
and harsh weather conditions that strongly
shape mortality. Thus, genes required for
maintenance, such as DNA repair, become
less important in short-lived killifish com-
pared with their long-lived counterparts
and are under relaxed selection ( 8 ).
Short-lived rockfish, which are smaller
and inhabit shallower waters than long-
lived rockfish, might confront more haz-
ards such as competitors, predators, and
pathogens. These factors could increase
the extrinsic mortality and thus lead to
a more relaxed selection in genes with a
beneficial role during late life stages, such
as DNA repair genes. By contrast, long-
lived rockfish are larger in size and inhabit
deeper parts of the ocean. Notably, the
fecundity of rockfish increases as a func-
tion of age, proportional to weight. For in-
stance, 150-year-old yelloweye rockfish can
produce more than 1 million offspring per
season. In this respect, extra investment
in DNA repair can protect the long-lived
rockfish from age-associated diseases and
substantially increase fecundity at older
ages, which would further facilitate the
positive selection of DNA repair genes.
Relaxed selection is correlated with ge-
nome expansion in killifish, which is mainly
attributable to transposable elements (TEs)
( 8 ). The activity of TEs can promote DNA
damage and genome instability that fur-
ther lead to aging and age-associated dis-
eases ( 10 ). Furthermore, activation of TEs
in humans and mice can drive interferon-
induced sterile inflammation, a hallmark
of aging in the mouse and human ( 11 , 12 ).
Hence, it will be interesting to see whether
TEs are involved in the regulation of lon-
gevity in rockfish.
Kolora et al. show an expansion of the
immunosuppressive butyrophilin gene
family in long-lived rockfish, suggesting a
tighter control of inflammation. Long-lived
rockfish may tolerate the reduced inflam-
matory function because of a decreased
abundance of microbes in the deeper
ocean. Inflammaging (increased systemic
inflammation with age) has emerged as
an important hallmark of aging, and evo-
lutionary strategies that reduce inflam-
mation favor longevity. Indeed, other
long-lived animals, such as bats, appear
to down-regulate inflammation through
diverse mechanisms. For example, the
PYHIN family of cytoplasmic DNA sensors
is absent in several bat species ( 13 ).
DNA CpG methylation has been used to
build epigenetic clocks to predict chrono-
logical age and biological age and to test
antiaging interventions ( 14 ). Kolora et al.
show that the evolution of different rock-
fish life histories reshapes the mutational
spectrum that drives CpG-to-TpG variants
(which can no longer be methylated) in
long-lived species. Given the key regula-
tory roles of the CpG sequence, it is unclear
what the genomic distribution of CpG-to-
TpG variants in long-lived species is—is it
genome-wide or at specific regions? Does it
alter gene expression?
The study of Kolora et al. presents rock-
fish as a distinct model that is long-lived
while maintaining high fecundity at old
age, thereby increasing selection of prolon-
gevity genes. Humans, despite being long-
lived, have relatively short reproductive life
spans and hence are susceptible to relaxed
selection of maintenance pathways at older
ages, contributing to age-associated dis-
eases (see the figure). Comparative biology
is a fruitful approach to study longevity.
Humans live longer than most vertebrates,
but long-lived rockfish can offer humans
strategies for improvement. Genetic ad-
aptations found in rockfish illustrate that
strategies that improve DNA repair and
control inflammation may extend life span
and health span. The genome assemblies
generated by Kolora et al. will enable fur-
ther studies of rockfish as a model of lon-
gevity. Yet genomic DNA sequence alone
cannot fully explain the aging process.
Although the DNA sequence is constant in
all cell types of a species, the gene regula-
tory network of each cell can vary consider-
ably, contributing to dynamic gene expres-
sion programs and biological functions.
Comparative transcriptomics, proteomics,
and metabolomics will reveal further layers
of aging and longevity regulation. jREFERENCES AND NOTES- W. D. Hamilton, J. Theor. Biol. 7 , 1 (1964).
- V. Gorbunova, A. Seluanov, Z. Zhang, V. N. Gladyshev, J.
Vijg, Nat. Rev. Genet. 15 , 531 (2014). - S. R. R. Kolora et al., Science 374 , 842 (2021).
- B. Schumacher, J. Pothof, J. Vijg, J. H. J. Hoeijmakers,
Nature 592 , 695 (2021). - B. Zhao, E. Rothenberg, D. A. Ramsden, M. R. Lieber, Nat.
Rev. Mol. Cell Biol. 21 , 765 (2020). - X. Tian et al., Cell 177 , 622 (2019).
- M. Keane et al., Cell Rep. 10 , 112 (2015).
- R. Cui et al., Cell 178 , 385 (2019).
- Tabula Muris Consortium, Nature 583 , 590 (2020).
- V. Gorbunova et al., Nature 596 , 43 (2021).
- M. Simon et al., Cell Metab. 29 , 871 (2019).
- M. De Cecco et al., Nature 566 , 73 (2019).
- V. Gorbunova, A. Seluanov, B. K. Kennedy, Cell Metab. 32 ,
31 (2020). - S. Horvath, K. Raj, Nat. Rev. Genet. 19 , 371 (2018).
10.1126/science.abm3392Department of Biology, University of Rochester, Rochester,
NY, USA. Email: [email protected]
BIOMATERIALSA dynamic duo
Self-assembly of nanofibers
facilitates the repair of
spinal cord injury in mice
B y Jonathan P. Wojciechowski
and Molly M. Stevens^T
he extracellular matrix (ECM) is a vi-
tal component of all tissues th at con-
tributes to the physical and chemical
cues that can affect cell fate. The
design of materials to encourage the
repair of tissue after injury is a long-
standing goal of regenerative medicine. Su-
pramolecular polymers based on reversible
noncovalent interactions form fibrous mate-
rials that can act as simple but tailored ECM
mimics. On page 848 of this issue, Álvarez
et al. ( 1 ) show that tuning the dynamics of
bioactive supramolecular polymers corre-
lates with the degree of regeneration and
functional outcome after acute spinal cord
injury (SCI) in mice.
Structurally, the ECM comprises a na-
noscale fibrous network composed of a com-
plex and dynamic collection of structural
proteins (e.g., collagen, fibronectin, and lam-
inin) along with glycosaminoglycans (e.g.,
heparin and hyaluronic acid) and signaling
proteins (e.g., growth factors and enzymes),
which are constantly being remodeled ac-
cording to interactions with the resident
cells. The signals provided by the ECM can
have multiple, sometimes opposing, roles
on the local tissue environment, beneficially
aiding regeneration of damaged tissue or,
conversely, negatively amplifying a diseased
tissue environment. This is especially true
after SCI, where a complex ECM microenvi-
ronment of proteins and proteoglycans can
inhibit axon regrowth but also act to isolate
the injury site, preventing further damage
( 2 , 3 ). This response contributes to the dif-
ficulties in treating SCI, emphasizing the
importance of understanding the role of the
ECM in tissue environments and of design-
ing synthetic mimics of the ECM to promote
regenerative cell behavior ( 4 ).
Supramolecular polymers are a promis-
ing class of materials that are composed of
well-defined monomeric subunits, which
self-assemble into nanofibers through re-
versible noncovalent interactions to form a
mesh-like network that structurally mim-Department of Materials, Department of Bioengineering,
and Institute of Biomedical Engineering, Imperial College
London, London, UK. Email: [email protected]