How much RAM do you have?
This explains the main tunables:
http://mysql.rjweb.org/doc.php/memory
You should consider moving from MyISAM to InnoDB.
key_buffer_size is much too big.
Add skip-bdb to MySQL configuration to disable BDB -- no big deal
Run OPTIMIZE TABLE to defragment tables for better performance -- This script is too eager to suggest this; generally OPTIMIZE is not needed. Do SHOW TABLE STATUS on the 12 fragmented tables - this will give some more clues of whether it _might_ be desirable.
Enable the slow query log to troubleshoot bad queries -- Yes
[OK] Slow queries: 0% (808K/7B)
Change long_query_time to 2 (or 1) to capture more of the slow queries.
Then use pt-query-digest to find the worst queries. Focus on them.
Your applications are not closing MySQL connections properly -- and...
Reduce or eliminate persistent connections to reduce connection usage -- You have hit max_connections at least once in the last 612 days.
Increase table_cache gradually to avoid file descriptor limits -- The data does not support this.
*** MySQL's maximum memory usage is dangerously high *** -- well, that depends on how much RAM you have.
innodb_buffer_pool_size (>= 66G) -- depends on RAM size
max_connections (> 1000) -- not the right solution
wait_timeout (< 86400) & interactive_timeout (< 600) -- lower them to bump idle users out.
Those two settings interact.
query_cache_limit (> 1M, or use smaller result sets) -- not enough info. See my link.
> MySQL version 5.0.77
That is rather old. Plan on upgrading.