Science - USA (2021-11-12)

824 12 NOVEMBER 2021 • VOL 374 ISSUE 6569

GRAPHIC: N. DESAI/

SCIENCE

science.org SCIENCE

The study by Gate et al. provides impor-
tant evidence from human patients for the
relevance of this immune pathway as a po-
tential disease-modifying therapeutic tar-
get for LBD. As this homing pathway is not
specific to the CNS, CXCR4 antagonists have
been developed and are effective in treat-
ing various immune-related conditions ( 13 ).
Nevertheless, it is worth considering the pos-
sibility that these immune cells are part of a
corrective response, rather than the cause of
damage. Uncovering the functional role of
CXCR4+ TH17 cells in disease etiology will al-
low the design of treatments to harness the
therapeutic potential of an effective immune
reaction. Indeed, the concept of autoimmu-
nity is undergoing a revision, because its ben-
eficial role in physiology has become increas-
ingly apparent. A recent theory proposes that
autoimmunity is targeted against regulatory
and secreting cells, such as b cells in the pan-
creas, to maintain endocrine regulation ( 14 ).
It will be interesting to consider how this
model could be extended to the nervous sys-
tem and whether autoimmunity is directed
more specifically to some types of neurons
(e.g., neuropeptide-secreting neurons).
The increasing evidence for the participa-
tion of immune mediators in various neu-
rodegenerative conditions, including LBD,
Alzheimer’s disease, and MS, strengthens
the need to understand the neuroimmune
dialogue in health and disease. Much of the
accumulated evidence comes from animal
models and suffers from the limitations of
such models and their relevance to humans,
highlighting the importance of the Gate et
al.  study. Moreover, because the clinical
manifestations of many neurodegenerative
diseases appear after substantial damage
has already occurred, it is critical to find bio-
markers, such as specific immune cells, that
define earlier stages of the disease. j

REFERENCES AND NOTES

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2. D. Sulzer et al., Nature 546 , 656 (2017).


3. D. Gate et al., Science 374 , 868 (2021).


4. K. Baruch et al., Nat. Med. 22 , 135 (2016).


5. A. Surendranathan et al., Brain 141 , 3415 (2018).


6. A. Peters, Y. Lee, V. K. Kuchroo, Curr. Opin. Immunol. 23 ,
   702 (2011).


7. E. Storelli et al., Front. Neurol. 10 , 13 (2019).


8. E. Kawamoto, S. Nakahashi, T. Okamoto, H. Imai, M.
   Shimaoka, Autoimmune Dis. 2012, 357101 (2012).


9. H. González, R. Pacheco, J. Neuroinflammation 11 , 201
   (2014).


10. S. Man et al., Sci. Transl. Med. 4 , 119ra14 (2012).


11. T. M. Calderon et al., J. Neuroimmunol. 177 , 27 (2006).


12. M. Li, J. S. Hale, J. N. Rich, R. M. Ransohoff, J. D. Lathia,
    Trends Neurosci. 35 , 619 (2012).


13. N. D. Stone et al., Antimicrob. Agents Chemother. 51 ,
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14. Y. K. Kohanim, A. Tendler, A. Mayo, N. Friedman, U. Alon,
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ACKNOWLEDGMENTS
The autho rs thank S. Schwarzbaum for help with the
manuscript.
10.1126/science.abm4739

AGING

Long-lived fish in a big pond

By J. Yuyang Lu, Andrei Seluanov,

Vera Gorbunova

B

ecause of competitors, predators,

pathogens, and other hazards, most

individuals in natural populations

die or are killed before they reach ad-

vanced age. In such a scenario, natural

selection does not act on genes that

are expressed at old age, a so-called selec-

tion shadow. As a result, genes and pathways

that are important for maintaining health at

advanced ages are not selected for, making

aging an inevitable product of evolution ( 1 ).

However, species have an amazing diversity

of life spans, which provide insights into the

mechanisms of aging and life span control

( 2 ). Some species of Pacific rockfish have

maximum life spans of up to 150 years and

are believed to lack age-associated decline.

On page 842 of this issue, Kolora et al. ( 3 ) as-

sembled the genomes of 88 rockfish species

to identify genetic drivers of longevity.

DNA damage accumulates throughout

life and has been implicated as a major

cause of aging ( 4 ). To minimize these le-

sions, a complex network that senses and

repairs DNA damage has evolved in various

organisms ( 5 ). Kolora et al. reveal that posi-

tively selected genes in long-lived rockfish

(those that live more than 105 years) are

enriched for DNA double-stranded break

repair pathways, whereas no gene pathway

was enriched in short-lived rockfish (those

that live less than 20 years). Longer-lived

mammals also maintain DNA better.  A

study of 18 rodent species with diverse

life spans revealed that more robust DNA

double-stranded break repair coevolves

with longevity ( 6 ). The difference in DNA

repair efficiency was largely due to a more

powerful version of a genome maintenance

gene, sirtuin 6 (Sirt6), in long-lived rodents.

The DNA repair genes that are positively

selected in the long-lived rockfish also un-

dergo positive selection in the bowhead

whale ( 7 ), whose maximum life span is

more than 200 years. Besides DNA repair,

genes involved in nutrient sensing show

lower evolutionary rates in long-lived rock-

fish. However, for another vertebrate model

in aging research, the short-lived African

killifish (which live less than 1 year), the ac-

cumulation of deleterious genetic variants,

or relaxation of selection, was observed in

genes involved in DNA repair and nutri-

ent sensing ( 8 ). Overall, studies of diverse

vertebrate species support DNA repair as a

longevity determinant.

Why are DNA repair and other longev-

ity genes positively selected in long-lived

rockfish but not in short-lived rockfish and

killifish? Living organisms experience DNA

damage throughout their life, which can

result in the accumulation of mutations

and epigenetic changes. Indeed, increased

Selection pressure

The force of natural selection

declines as a function of age

in killifish and humans, but

not in rockfish.

Longevity genes

Rockfish and killifish show distinct selection

patterns of longevity-regulating genes.

FEN1, 
ap structure-specific endonuclease 1; FOXO1, forkhead box O1; IGF1, insulin-like growth factor 1; INSR, insulin-like growth factor 1 receptor;

MSH, mutS homolog; mTOR, mechanistic target of rapamycin; WRAP53, WD repeat containing, antisense to TP53.

Longe

Rockfish and

patterns

Force of natural selectionKillifish

KILLIFISH

Humans

Onset of

age-related

diseases

Selection

shadow

Age

Rockfish ROCKFISH

Stable environment

Low adult mortality

Changing environment

High mortality

Positive

selection

(FEN1,

WRAP53,

etc.)

DNA repair

Relaxed

selection

(MSH2,

MSH6, etc.)

Low evolutionary

rate (IGF1,

FOXO1, etc.)

Nutrient

sensing pathways

Relaxed

selection

(mTOR,

INSR, etc.)

Expansion of

immunosup-

pressive genes

(butyrophilins)

Immunity

Loss of

immunity

genes

Evolution of longevity genes in species with different life strategies

The genetic drivers of extreme longevity in Pacific Ocean

rockfish are identified

INSIGHTS | PERSPECTIVES