Klotho Increasing Stratégie (KIS)

Over 125 separate active agents have been identified, each with some level of ability to increase systemic levels of Klotho. This page describes a targeted list incorporating a synergistic [₪], strategy for activating the Klotho Gene and/or increasing the circulating levels of soluble Klotho. The following classes of active agents have been identified; Supplements, Antioxidants, Nutraceuticals, Vitamins, Minerals, Trace Metals, Drugs and Small Molecules.

Six categories of interventional opportunities have been identified: 1) Agents that directly upregulate Klotho expression;  2) Agents that upregulate upstream molecular pathways known to activate Klotho;  3) Antioxidants that are direct scavengers or produce a secondary antioxidant environment;  4) Demethylation agents that re-expose the DNA promoter reagon of Klotho; 5) Agents that facilitate signal transduction by increasing binding kinetics facilitating the interactions between active agents that modulate Klotho and the regulation of molecular pathways; 6) Synergistic combinations of agents often crossing agent classifications and/or categories. 

Each active agent and the overridding strategic goal is supported by extensive support in the literature, demonstrating the ability of each agent to increase Klotho levels.  Because of the significant differences between product formulations, bioavailability, dosing, and interval of dosing, this page can only identify effective candidates and/or effective combinations to be potentially included in a Klotho increasing strategy.  A regimen of specific active agents can not be provided at this point in time. Hopefully the information provided on these page will provide the building blocks required to get to that goal in the near future.  To date the majority of all studies have been carried out in small animal models or cellular assays.  Laboratory markers that would provide reliable and reasonably priced feedback are also lacking.  Klotho assays are unavailable at all commercial laboratories I have communicated with. Surrogate indicators that would provide feedback enabling the modification of the active agents identified on these pages are also limited to research institutions. 

A more effective method entails testing all available combinations in small animal models to ascertain the most potent combinations utilizing clinical, laboratory, health markers and longevity. While it is hoped that those with necessary resources will delve into such research, financial incentives to conduct this research is limited. The KIS project is currently confined to peer-reviewed research and ChatGPT, a large language model developed by OpenAI. There are no human clinical trials of this strategy, but multiple interventional studies with the goal of increasing Klotho levels of proprietary candidates are beginning.

Upon mapping the Klotho molecular pathways, the next phase of the process focuses on identifying the active agents that can directly up-regulate the expression of Klotho and/or lead to the appropriate regulation of the relevant Klotho signaling pathways. Over the last six months, an exhaustive search through Public-Med and Google Scholar for such agents has led to the identification of over 125 Klotho activating agents.  The complete list is available for download at the bottom of this page. Klotho has recently re-emerged as a keen area of interest for many research groups and biotechnologies resulting in a great deal of current and relevant research results becoming publicly available. The agents identified have all show the potential to either directly up-regulate Klotho or modulate the upstream pathways, resulting in the downstream activation of Klotho. A subset of these agent have been identified demythelation agents, inducing epigenetic modifications facilitating the expression of Klotho. A recent publication has established a very strong correlation between Klotho levels and administration of antioxidants. It in all probability point to a strong secondary mechanism of action that many of these agents have in common.

[2023] Composite Dietary Antioxidant Index and Plasma Levels of Soluble Klotho- Insights from NHANES

Within the context of the KIS stratgie, the spreadsheet described below aids in the identification, integration, and stratification of the most effective agents. Out of 125 agents identified, the spreadsheet currently highlights 25, based on current research and two scoring criteria. This screening tool not only enables you to easily match the molecular pathways modulated by an active agent, but also provides insights into the potential synergistic potentiation of agent combinations. By refining and ranking an optimal set of agents, the process becomes more streamlined and focused on agents capable of effectively elevating Klotho levels.  

Header Keys are provided above and on the right. Target-Agents were ranked (A) based on their potential to regulate Klotho expression through 15 specific molecular pathways. (Header of this spreadsheet is shown above) Of over 30 pathways associated with Klotho, these 15 were selected for their strong influence or direct regulatory influence. An effectiveness score is produced by counting how many of these 15 pathways are appropriately (activated or inhibited) by each Target-Agent (F) (Blue background with white text). For instance, curcumin positively modulates all 15 pathways, and represents a strong Klotho enhancing Agent.

The checkmark, ☑️ (C) indicates that this agent is currently a candidate for inclusion in a combinational approach to increasing systemic levels of Klotho.

Another assessment evaluates each Target-Agent's concomitant performance alongside other agents (G). During our research a comprehensive inventory of agents that are additive, complementary or synergistic have been compiled. ChatGPT was also incorporated to assist in organizing and mapping these agents to a parent agent. This score is shown below the pathway influence score (White background with black text). Each of these agents are listed on the spreadsheet by parent agent and stratified by individual molecular pathways. 

The KIS Spreadsheet also identifies strong antioxidants and demethylating agents by the following flag conventions.

• A white dot in a red box (B) signals an agent with strong antioxidant properties.

• A red border around the agents name, indicates the agent is a de-methylating agent (E).

ChatGPT was utilized to screen, organize and stratify the rankings of the identified active agents incorporated into this strategy.  A paper is available for download at the bottom of this page describing the “grounded truth,” technique that dramatically improves the accuracy of AI bot responses. The actual prompts used, along with an example prompt response, are also available for download at the bottom of this page.   If you utilize the provided prompt and discover something relevant to our goals,  please share them with us using the “Contact,” link at the bottom of this page.                                            [Download-3]    [Download-4]    [Advanced Prompt Design]

KIS Google Spreadsheet

Our approach to elevating systemic Klotho levels is multifaceted, targeting both Klotho itself and specific pathways known to enhance its expression. We aim to emulate natural processes that activate the Klotho gene by selecting multiple synergistic agents that influence multiple pathways. Fewer active compounds are required when combining complementary or synergistic agents, thereby achieving a more robust and safer response. Agents such as Vitamin C, Magnesium, and Zinc prepare the system for optimal signaling, and due to their antioxidant capacities, many agents can significantly boost Klotho levels both as primary and secondary response modifiers. The KIS spreadsheet primarily matches each agent's ability to regulate molecular pathways, correlating with the ideal signaling pressures identified by the first line (A through O). By integrating this information, we can swiftly pinpoint potentially potent interventional opportunities.

◉  Anyone who has information, personal insights or suggestions that would benefit our goal of increasing systemic levels of Klotho, please contribute your insights and perspectives using the contact button at the bottom of this page.