Autophagy is responsible for cellular self-digestion that recycles intracellular components and for trafficking events that activate innate and adaptive immunity as well as autoinflammatory diseases [1]. Senescence is the cease of cellular division without cell death activation, and immune-senescence is a series of age-related changes that affect the immune system [2], including a decline in coping with proinflammatory status [3]. Normally, functioning autophagy protects against neurodegeneration associated with intracytoplasmic aggregate-prone protein accumulation, in addition to its other roles, such as neuronal stem cell differentiation [4]. Neurodegenerative disorders share common pathogenic mechanisms, including the impairment of autophagic flux, which prevents the removal of neurotoxic misfolded proteins; effective disease-modifying strategies seek novel molecules exhibiting pro-autophagic potential [5].

Senescent cells are a major contributor to age-dependent cardiovascular tissue dysfunction and the integration of transcriptomes of senescent cell models representing multi-tissue patient samples has revealed that reduced collagen type VI alpha 3 chain (COL6A3) expression is one of the triggers of senescence [6]. Senescent cells represent a pharmacologic target for alleviating geriatric decline and chronic diseases [7]. Senolytic drugs like dasatinib, quercetin, fisetin, and navitoclax, were discovered using a hypothesis-driven approach; early pilot trials of senolytics suggest they decrease senescent cells, reduce inflammation, and alleviate frailty in humans [8]. Increased post mitotic senescence in aged human neurons is a pathological feature of Alzheimer’s disease; senescent neurons gain an inflammatory senescence-associated secretory phenotype (SASP) and can be eliminated with senotherapeutics [5]. Microbiota sensing—free fatty acid receptor 2 signaling ameliorates amyloid-β induced neurotoxicity—can be activated by modulating proteolysis-senescence axis [9].

It has been shown that plants and fungal metabolites possess antiaging properties, and compounds isolated from plants and fungi modulate the cellular and physiological pathways that prolong lifespan and prevent age-related diseases in model organisms [10]. These compounds act through cellular processes such as autophagy and senescence and as such delay aging and prevent chronic diseases [11]. When autophagy is impaired, waste derived from tissue damage leads to organ deterioration. Thus, autophagy plays a critical role in antiaging processes and mTOR plays an important role in inhibiting autophagy. A chemo-informatics study of phytochemicals, using docking and molecular dynamics simulation, identified, among other compounds, the cyclo-trijuglone of Juglans regia L. as a potential ATP-competitive inhibitor of mTOR [12]. Senolytic compounds that selectively clear senescent cells, such as dasatinib, quercetin, fisetin and navitoclax, were discovered using a hypothesis-driven approach [8]; flavonoids quercetin and fisetin are found in fruits and vegetables [13] and have the potential to reduce the factors secreted by senescent cells (SASP) that lead to chronic inflammation and deterioration of healthy organs [14]. Recent in silico analysis of metabolites secreted by senescent cells may serve as tools to identify senescence inhibitors (SI) based on the mechanism of action [15].

Autophagy and cellular senescence serve as stress responses to mammalian cells but the interconnection between these pathways is complex: autophagy sometimes suppress cellular senescence by removing damaged macromolecules or organelles, and in different scenarios, autophagy leads to cellular senescence and synthesis of SASPs [16]. Although autophagy and senescence interconnection may influence very different processes such as stem cells [17], aging, and cancer [18, 19], autophagy activators could be exploited to prevent the induction of senescence and drugs targeting the process of autophagy can indirectly contribute to blocking the process of senescence [18]. Autophagy and senescence converge in inducing triggers and signaling pathways such as the AMPK signaling pathway [20]. And autophagic degradation of the inhibitory p53 isoform Δ133p53α acts as a regulatory mechanism for p53-mediated senescence [21].

Autophagy regulates senescence and pathogen-induced cell death in plants [22]. This basic knowledge suggests that together, autophagy inducers (AI) and SI can contribute to healthy aging in humans through various cellular mechanisms.

Fungi (phytopathogenic or mycorrhizal) that interact with plants depend on autophagy as a mechanism that is responsible for recycling cell components, for the interaction of fungus-plant [23], and for affecting the pathogenicity potential of plant pathogens [24]. Several examples from the literature will be discussed below.

Dasatinib, quercetin, and fisetin were identified as the 1st senolytic drugs derived from plants and fungi; they activate apoptosis of senescent cells and as such extend lifespan using animal models [31]. They may be effective in delaying human aging and treating chronic diseases.

Desert plants have adapted to stressful environments by synthesizing secondary metabolites and accumulating ions as osmoticum (a substance that acts to supplement osmotic pressure in a cell). Desert environments are one of the harshest places on earth due to low precipitation, limited soil nutrients, and high irradiation. The predictive metabolomics of multiple Atacama plant species unveils a core set of generic metabolites for extreme climate resilience [44]. The mechanisms to survive in harsh conditions suggest that these plants have generated unique metabolites, termed here by us “the wisdom of the desert” [45]. Studies showed variations in flavonoid metabolites along an altitudinal gradient in the desert medicinal plant Agriophyllum squarrosum [46]. Phytochemical analysis of secondary metabolites (alkaloids, terpenoids, tannins, saponins, flavonoids, and phenolics) in 26 plants from the desert of Egypt showed that flavonoids, phenolics, and tannins were present in all the examined species while saponin and terpenoid compounds were detected only in fifteen species. Such a resource of natural metabolites of plants, used traditionally for treatment, may be considered a new, biologically active source of medicinal compounds [47]. Among them, one can be expected to find AI and SI.

The harsh conditions of the desert also influence the biosynthesis of metabolites in fungi and microbes. Bioactive secondary metabolites from endophytic strains of Neocamarosporium betae, Chaetomium globosum (Chaetomiaceae), and Rhinocladiella similis collected from desert plants could be a new resource for bioactive natural products [48–50].

Filamentous cyanobacteria use unique extracellular polysaccharide-based biosynthetic pathways to survive in the desert. In addition to the extracellular polysaccharide, chaperones (to maintain protein integrity), oxidative stress protection system, synthesis of compatible solutes and ion channels, and upregulation of DNA repair mechanism are examples of the strategies cyanobacteria use for coping with desiccation/rehydration cycles in the desert [51]. These metabolites that facilitate the adaptation to extremely arid environment may contain potential AI and SI. Analysis of Sonoran desert fungi (Aspergillus strains) occurring in the rhizosphere of Ambrosia ambrosoides and in the rhizosphere of Anicasanthus thurberi, identified unusual new secondary metabolites terrequinone A, terrefuranone and 4R,5S-dihydroxy-3-methoxy-5-methylcyclohex-2-enone, 6-methoxy-5(6)-dihydropenicillic acid, respectively, with medicinal properties like selective toxicity against cancer cells (and not against healthy cells) [52]. These metabolites that enable growth in harsh arid environments may contain potential AI and SI.

Novelty: Many novel AI and SI are waiting to be discovered in plants, fungi, and microbes. As aging is characterized by systemic chronic inflammation, which is accompanied by impaired autophagy and by cellular senescence (including SASP), elimination of inflammation could be a potential healthy aging strategy. Table 1 summarizes the suggested mechanism of action of AI and SI discussed in this Perspective.

Challenges (before moving to clinical trials in humans): i. Suitable in vitro and in vivo models are needed for screening the novel agents for toxicity/safety dosage, mode of application, efficacy, and selectivity. ii. Understanding of the underlying mechanisms linking autophagy, senescence, inflammation, and aging will enable optimization of therapeutic strategies.