Longevity

Scientists Develop New Anti-Aging CRISPR-Based Gene Therapy

Kat7 gene inactivation rejuvenates prematurely aging human cells and mice and promotes longevity.

(Meletios Verras | iStock)
By Noemi Canditi

Highlights

  • Wang et al. conducted a genome-wide CRISPR-Cas9–based screen to identify genes that could affect cellular senescence.
  • They identified KAT7 as a driver of senescence in human adult stem cells.
  • Inactivation of KAT7 rejuvenated prematurely aging progeroid human cells and extended the life span of mice.

Whereas cellular senescence — a state of permanent growth arrest — is known to advance aging, how this process occurs remains unclear. Our understanding of what drives cellular senescence is instrumental in developing interventions to promote anti-aging and longevity.

Wang and colleagues from the Chinese Academy of Sciences in Beijing published an article in the journal Science Translational Medicine where they mined for genes that could affect cellular senescence. They sieved DNA from human cells modeling aging with the gene-editing tool CRISPR for genes whose deficiency alleviated cellular senescence. This screen yielded KAT7, which, when inactivated, led to the rejuvenation of prematurely aging human cells. When they disabled KAT7 in mice aging normally and prematurely, the lifespan of both the rodents was prolonged.

This study zeroes in on KAT7 as a therapeutic target for developing anti-aging interventions and adds to the evidence that CRISPR-based gene editing can be used to promote longevity. “Our study adds another example showing the possibility of using gene therapy for antagonizing aging and aging-related disorders,” said the authors in their article.

Slowing cellular senescence in humans

Aging is a seemingly inevitable process that causes a functional decline in nearly all organisms. Cellular senescence has recently emerged as both a hallmark of aging and a fundamental driver of the aging processes. Senescent cells accumulate in tissues over time, triggering natural features of organismal aging and contributing to aging-related diseases like arthritis and Alzheimer’s.

Senescent cells aren’t just indicative of aging; these non-replicating cells play a causative role in organismal aging. For example, senescent cells gradually accumulate in the degenerated liver, whereas clearing senescent cells from the liver attenuates the development of hepatic steatosis (or fatty liver disease). So, delaying or reversing cellular senescence may provide a new therapeutic approach for treating aging-related disorders.

Although we’re becoming more privy to what happens to the human body as we age, most of what we know about the genes that play a role in aging originates from experiments using short-lived model organisms, such as yeast, worms, flies, and fish. Therefore, elucidating the genetic programs that govern human aging remains an important goal.

Screen identifies new human senescence-promoting genes

Wang and colleagues used the powerful genetic engineering tool CRISPR to delete little bits of DNA to identify genes affecting aging using two types of human cells exhibiting accelerated senescence. These cells carried disease-causing mutations that cause premature aging diseases Werner syndrome (WS) and Hutchinson-Gilford progeria syndrome (HGPS). The research team identified genes whose deficiency alleviated cellular senescence, including KAT7, which ranked as a top hit in both the WS and HGPS premature aging human cell models.

(Wang et al. 2021 | Sci Transl Med) KAT7 inactivation by CRISPR gene editing rejuvenates Werner syndrome adult stem cells. KAT7 deficiency (sg-KAT#1 and sg-KAT#2) substantially increased the proliferative potential of adult stem cells modeling Werner Syndrome (WS) without KAT7 deficiency (sg-NTC) to levels of typical, non-mutated cells (WT) (Left). KAT7 deficiency alleviated multiple premature aging features previously identified in WS adult stem cells, as evidenced by the following findings: (i) increased percentage of replicating (Ki67-positive) cells (middle); (ii) decreased percentage of senescent (SA-β-gal–positive) cells (right).

To investigate whether KAT7 deficiency alleviated senescence, Wang and colleagues targeted KAT7 for gene silencing by CRISPR in WS, HGPS, and replicative-senescent adult stem cells. They found that KAT7 ablation in all three models improved proliferative potential and alleviated aging features. Furthermore, the ablation of KAT7 alleviated senescence models of cancer, UV, and oxidative stress. These findings indicate that KAT7 depletion attenuates senescence in diverse biological contexts.

Lastly, Wang and colleagues wanted to test out the anti-aging CRISPR gene therapy approach in living animals. So, the researchers tested the effect of inactivating KAT7 with CRISPR in mice aged naturally and prematurely. Using viruses to deliver CRISPR components to inactivate KAT7, given intravenously, the researchers saw that this alleviated liver cell senescence and liver aging as well as extended life span in mice aged both naturally and prematurely. Although promising, these effects were not seen in other organs because the researchers only found the gene-editing of KAT7 occur in the liver likely due to the viral treatment method. Future studies will need to examine the consequences of targeting KAT7 in more cell types or specific organs to define the function and safety scope of KAT7 intervention.

(Wang et al. 2021 | Sci Transl Med) Gene therapy targeting KAT7 extends health span and life span in naturally aged mice. Survival curve (left) of naturally aged mice infected virus-carrying CRISPR targeting components for KAT7 (sg-Kat7; green) or non-specific DNA (sg-NTC; grey) at 20 months. Survival curve (right) of prematurely aging (Zmpste24−/−) mice infected with CRISPR components targeting KAT7 (sg-Kat7) or non-specific DNA (sg-NTC) virus.

Can CRISPR be used as an anti-aging treatment?

“Our study adds a layer of complexity to KAT7 function by revealing its important role in aging biology and pinpointing KAT7 as a new target for delaying aging and treating aging-associated disorders,” said the authors in the article. “In addition to unraveling the role of KAT7 in mediating aging, our screen identified additional senescence genes that might be targeted to ameliorate aging-related processes.”

Moreover, this study shows that CRISPR-based gene editing can inactivate senescence genes like KAT7 to rejuvenate human cells. Although this anti-aging therapeutic strategy is promising, it is too soon to tell if these CRISPR-based techniques will be effective in humans to improve healthspan and longevity.

Source

Wang W, Zheng Y, Sun S, Li W, Song M, Ji Q, Wu Z, Liu Z, Fan Y, Liu F, Li J, Esteban CR, Wang S, Zhou Q, Belmonte JCI, Zhang W, Qu J, Tang F, Liu GH. A genome-wide CRISPR-based screen identifies KAT7 as a driver of cellular senescence. Sci Transl Med. 2021 Jan 6;13(575):eabd2655. DOI: 10.1126/scitranslmed.abd2655. PMID: 33408182.

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