FOXOs regulate p21 Cip1 , a prominent factor in senescence growth arrest, and they inhibit the stemness regulator β-catenin. As such, they could be ideal therapeutic targets to counter senescence, while promoting tissue rejuvenation.

Senescent cells can impair their environment through juxtacrine and paracrine signaling of SASP factors. This may be caused by keeping neighboring cells permanently locked in a state of dedifferentiation (Figure 3), leading to reduced tissue rejuvenation potential.

Cell-penetrating peptides can steer very specific protein–protein interactions and have been successful in various clinical trials. They are a potent option for forward design of antisenescence therapies.

Viability screens with existing compounds lead to discovery of the first generation of antisenescence compounds as quercetin/dasatinib and pan-BCL inhibitors. Further optimization is required due to suboptimal selectivity or toxicity.

Semigenetic clearance of senescent cells delays features of aging in fast and naturally aged mice establishing senescence as their underlying cause.

The potential to reverse aging has long been a tantalizing thought, but has equally been considered mere utopia. Recently, the spotlights have turned to senescent cells as being a culprit for aging. Can these cells be therapeutically eliminated? When so? And is this even safe? Recent developments in the tool box to study senescence have made it possible to begin addressing these questions. It will be especially relevant to identify how senescence impairs tissue rejuvenation and to prospectively design compounds that can both target senescence and stimulate rejuvenation in a safe manner. This review argues that to fulfill this niche, cell-penetrating peptides may provide promising therapeutics. As a candidate approach, the author also highlights the potential of targeting individual FOXO signaling pathways to combat senescence and stimulate tissue rejuventaion.

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A first-in-class, first-in-human, phase I trial of p28, a non-HDM2-mediated peptide inhibitor of p53 ubiquitination in patients with advanced solid tumours.

Efficacy and safety of AM-111 in the treatment of acute sensorineural hearing loss: a double-blind, randomized, placebo-controlled phase II study.

Subconjunctival injection of XG-102, a JNK inhibitor peptide, in patients with intraocular inflammation: a safety and tolerability study.

Molecular dynamics simulations suggest a mechanism for translocation of the HIV-1 TAT peptide across lipid membranes.

Biochemical and structural characterization of an intramolecular interaction in FOXO3a and its binding with p53.

p53-mediated senescence impairs the apoptotic response to chemotherapy and clinical outcome in breast cancer.

p21 modulates threshold of apoptosis induced by DNA-damage and growth factor withdrawal in prostate cancer cells.

FoxO transcription factors in the maintenance of cellular homeostasis during aging.

Activation of IL6/IGFIR confers poor prognosis of HBV-related hepatocellular carcinoma through induction of OCT4/NANOG expression.

Early role for IL-6 signalling during generation of induced pluripotent stem cells revealed by heterokaryon RNA-Seq.

Cell surface-bound IL-1alpha is an upstream regulator of the senescence-associated IL-6/IL-8 cytokine network.

Chronic interleukin-1 exposure drives haematopoietic stem cells towards precocious myeloid differentiation at the expense of self-renewal.

The unfolded protein response and cellular senescence. A review in the theme: cellular mechanisms of endoplasmic reticulum stress signaling in health and disease.

Senescence-associated heterochromatin foci are dispensable for cellular senescence, occur in a cell type- and insult-dependent manner and follow expression of p16(ink4a).

Tumor suppressor and aging biomarker p16(INK4a) induces cellular senescence without the associated inflammatory secretory phenotype.

Mitochondria are required for pro-ageing features of the senescent phenotype.

Nanoencapsulation of ABT-737 and camptothecin enhances their clinical potential through synergistic antitumor effects and reduction of systemic toxicity.

Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity.

Bcl-xL-inhibitory BH3 mimetics can induce a transient thrombocytopathy that undermines the hemostatic function of platelets.

An immunohistochemistry study of tissue bcl-2 expression and its serum levels in breast cancer patients.

Detailed tissue expression of bcl-2, bax, bak and bcl-x in the normal human pancreas and in chronic pancreatitis, ampullary and pancreatic ductal adenocarcinomas.

Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer.

Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL.

The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs.

Opposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency.

Age-associated increase in cytokine production during systemic inflammation: adipose tissue as a major source of IL-6.

Accelerated aging pathology in ad libitum fed Xpd(TTD) mice is accompanied by features suggestive of caloric restriction.

Senescence is a developmental mechanism that contributes to embryonic growth and patterning.

Overexpression of Il6 leads to hyperinsulinaemia, liver inflammation and reduced body weight in mice.

Bypass of senescence after disruption of p21CIP1/WAF1 gene in normal diploid human fibroblasts.

Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a.

An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA.

Bioluminescence imaging captures the expression and dynamics of endogenous p21 promoter activity in living mice and intact cells.

Glossary

pan-inhibitors of the BCL family of antiapoptotic guardians: BCL-2, BCL-XL, and BCL-W.

broad summary of diseases that mostly manifest at older age.

progressive loss of tissue function over time. Often attributed to accumulated cellular DNA damage.

secreted factor from cells triggering an immune response in the environment.

one cause having opposing consequences. In case of senescence, these are beneficial effects early in life and during wound healing (transient), while deleterious late in life (chronic).

a turn-over mechanism of cells to recycle unnecessary or dysfunctional cellular components, resulting in energy and building blocks.

a class of therapeutics making use of peptide sequences to pass a membrane and deliver a cargo. Common membrane-passing sequences involve the TAT sequence of HIV.

inhibitor of the Src family of kinases.

family of transcription factors with prominent roles in aging/longevity, growth/stress signaling, and differentiation/stemness. Can regulate expression of p21Cip1 together with p53 and stemness signaling through interaction with β-catenin.

theory suggesting that low, but chronic, levels of inflammation can drive an age-related decline in function.

a construct driven by part of the p16ink4a promoter containing enchanced green fluorescent protein and a version of caspase-8, which is activatable by the drug AP20187. Using this construct, p16ink4a-positive senescent cells can be visualized and eliminated by this drug. As elimination only occurs in cells carrying this construct, it is semigenetic.

an interleukin that is responsible for activation of much of the SASP and can be considered a master regulator.

prominent SASP factor (also activated by other processes) that can have strong implications on tissue function when highly expressed.

stress response in cells and tissues that are initially deprived from oxygen (ischemia), followed by sudden reflux (reperfusion). A common process during organ transplantation.

the length for which an organism lives.

a stem cell marker indicating pluripotency.

3D cultures mimicking a mini organ for in vitro culture.

a construct driven by part of the p16ink4a promoter containing Renilla luciferase (for bioluminescence), red fluorescent protein (for fluorescence), and thymidine kinase (TK) from the herpes simplex virus. The latter can phosphorylate a substrate ganciclovir (GCV). When GCV is added and taken up by cells it is incorporated into the DNA without apparent negative effect. Phosphorylation by TK however results in double-strand breaks and cell death. GCV addition would thus eliminate p16ink4a-positive senescent cells carrying this construct.

protein expressed from (part of) the CDKN2A locus. It is an inhibitor of the cyclin-dependent kinases (CDKs) 4/6, and its expression results in dephosphorylation and activation of the retinoblastoma tumor suppressor pRb, which inhibits E2F-mediated S-phase transition in the cell cycle and a persistent cell cycle arrest. Detected in the majority of senescent cells, though not all. Often used marker for senescence.

protein expressed from (part of) the CDKN1A locus. Transcriptional target of the p53 tumor suppressor in response to DNA damage. Often activated in senescent cells, but also after acute DNA damage. Can induce cell cycle arrest and has prosurvival functions.

having the ability as a cell to differentiate into other types of cells during a senescence-stem lock.

a flavonoid found in various fruits and vegetables.

drug-induced removal of senescent cells through the use of a construct expressed in these cells. Two examples are INK-ATTAC and p16::3MR.

chronic stress response after irreparable damage, associated with a state of persistent growth arrest and often an SASP. The growth arrest can be maintained by chronic expression of p16ink4a (predominantly) or p21Cip1 and potentially others.

the persistent secretion phenotype, which causes senescent cells to influence their environment. Most, but not all, senescent cells develop an SASP. The composition is heterogeneous per cell and type of senescence.

Cells that reside in a senescent state.

proposed model on how senescent cells may impair the function and rejuvenation of their environment by inducing a persistent state of pluripotency in neighboring cells. Individual SASP factors such as IL6 have been shown to induce reprogramming to pluripotency. As SASP secretion by senescent cells is chronic, this state would be permanent, causing these cells to be ‘locked’ in their stemlike state.

stress response activated by misfolded proteins, for instance after oxidation, leading to activation of chaperones and heat-shock factors to induce proper (re)folding.