**7. Study Limitations**

Although we have tried to emphasize the beneficial effects of ECS on various pathological mechanisms involved in multiple aging-related diseases, a series of limitations of this comprehensive review must be also discussed. For example, the contribution of genetic factors, as well as various influences from living environment which definitely influence the physiology of aging were not sufficiently take into account in this review [401,402]. In addition, various drug formulation and dosage as well as multiple adverse psychiatric reactions may also be considered as limitations of this study [403,404]. Therefore, from a pharmacokinetic point of view, cannabinoids are difficult to be managed in both animal and human studies since their absorption may vary. Furthermore, during chronic administration, cannabinoids may lead to drug tolerance which usually requires the increase of daily dosage with subsequent rise of psychiatric secondary effects [405]. These limitations hamper the translation of the results from experimental studies to daily clinical practice.

#### **8. Conclusions and Perspectives**

The cannabinoid system has the potential to ameliorate different underlying mechanism involved in the progression of aging-related diseases. Additionally, ECS may represent a promising approach not only for the treatment, but also for the alleviation of age-related disorder-associated symptoms and/or for increasing the efficacy of existing drugs. Moreover, our findings show that cannabinoids may be able to modulate various mechanisms rather than targeting a single dysregulated pathway in age-related diseases. Natural as well as synthetic cannabinoids ameliorate the balance between neurodegeneration and neuroinflammation in neurodegenerative diseases. In addition, they may play an important role in modulating the complex physio-pathology of MS and may be used as immune modulators, neuroprotectors, or remyelination promoters. The modulation of pro-inflammatory

cytokines through the endogenous cannabinoid system may have beneficial effects on MS, AD, PD, aging-related musculoskeletal changes, and CVDs. On the other hand, it is clearly now that targeting the ECS with various natural or synthetic compounds may have the theoretical potential of an improved control of cancer progression.

Although a plethora of scientific advances on the functional relevance of cannabinoids in age-related diseases was recently achieved, a series of outstanding research questions still remain. We strongly believe that further experimental studies are mandatory to encourage the translational approach to clinical trials assessing the therapeutic potential of cannabinoids in various aging-related diseases.

**Author Contributions:** Conceptualization: I.M.T. and B.I.T.; methodology: I.M.T., B.I.T. and I.T.; writing—original draft preparation: I.M.T., G.D.S., C.C., M.C., A.S., B.I., A.B., E.R., T.A.-S., I.C. and I.T.; writing—review and editing: I.M.T., I.T. and B.I.T.; visualization: I.M.T., G.D.S., C.C., M.C., A.S., B.I., A.B., E.R., T.A.-S., I.C. and I.T.; project administration: I.M.T. and B.I.T. All authors have read and agreed to the published version of the manuscript.

**Funding:** This work was supported by a gran<sup>t</sup> of the Romanian Ministry of Education and Research, CNCS–UEFISCDI, project number PN-III-P4-ID-PCE-2020-1247, within PNCDI III.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Conflicts of Interest:** The authors declare no conflict of interest.
